Relationships of Immunology to Cancer: a Review *

CANCER RESEARCH

VOLUME 20 APRIL 1960 NUMBER 3

Relationships of Immunology to Cancer: A Review *

CHESTER M. SOUTHAM

(Division of Clinical Chemotherapy, Sloan-Kettering Institute/or Cancer Research; Medical Service, Memorial Center; Medical Service, James Ewing Hospital; and Sloan-Kettering Division, Cornell University Medical College, New York, N.Y.)

CONTENTS 4. Indirect immunologic technics I. Introductionâ€”Immunology defined @71 C. Prognostic tests in cancer II. Review of host defense mechanisms D. Cancer treatment A. General VI. Conclusion @286 B. Cellular defense mechanisms C. Noncellular defense mechanisms I. INTRODUCTION 1. Nonspecific mechanisms The term immunology brings to my mind the @2.Specific mechanisms word glory, for glory is the word concerning which D. Factors indirectly affecting immune Jlumpty Dumpty exclaimed â€œaword means just phenomena what I want it to meanâ€”neither more nor less.â€• 1. Heredity The term immunology will be used here to em @2.Hormones brace all those biological mechanisms by which a 3. Nutrition metazoan organism resists the pathogenicity of 4. Age any noxious foreign thing. This broad definition is III. Antigenic analysis @275 stressed because the term immunology is some A. Methods of antigenic analysis times used as synonymous with serology or even 1. Immunologic technics to refer to antigen-antibody phenomena alone. In @2.Purification of antigens considering immunology as related to oncology 3. Choice of experimental host we must not restrict our survey, because we are IV. Are there host defenses against cancer? 9277 still groping for the mechanisms of resistance to A. Clinical observations suggestive of cancer; in fact, we are still searching for proof that host defenses against cancer defense mechanisms against the neoplastic process B. Experimental studies suggestive of do exist. Although our knowledge of immunology host defenses against cancer as related to cancer is inprecise and often specula V. Implications of immunology for clinical tive, it is nevertheless worthy of our consideration oncology @279 if for no better reason than that it demands the A. Cancer preventionâ€”theoretical con recognition of cancer as not merely a tissue or a siderations cell but as a dieease. Disease results from the inter B. Cancer detection action of a host and a pathogenic force, and thus 1. Serum antibody any consideration of immunology in relation to @. Skin tests cancer carries with it the implication that the host 3. Circulating antigens (the cancer patient) is not necessarily a passive

* Based on a talk presented at the Division of Medicinal supporter and victim of the neoplastic growth but Chemistry at the 134th meeting of The American Chemical may react to its presence. Any reaction of the host Society, Chicago, September 11, 1958. which tends to be detrimental to the continued Received for publication October 5, 1959. growth of the cancer may be considered a defense @71 Thia One

T4OS-CBF-0987

mechanism and comes within the broad field of phagocytosis (1@8). The fibroblast is an impressive immunology. but mysterious cell which, like Zorro or Superman, This review will attempt to consider this entire is inconspicuous or even unidentifiable in ordinary field. In such an undertaking omissions are in life but jumps into effective action when need evitable, and inequities in emphasis are unavoid arises, surrounding areas of injury by an increas able because of the personal interests and preju ingly dense tissue barrier or capsule which mechan dice of the author. For such, tolerance is requested. ically limits the extent of pathology. Lymphocytes Since references to such a massive literature can or plasma cells or both are producers of antibodies, not be complete, the attempt has been to include They do not directly attack foreign agents but such references as will in turn guide the interested probably accept into themselves particles of the reader to a more ample coverage of the literature. foreign material (antigen) and may synthesize or References to previous reviews are therefore fre@ modify a pro-existing globulin molecule in such quently made, and references to original work are fashion that it will combine specifically with and used for more recent or less extensively surveyed usually to the detriment of that foreign substance. reports, or when documentation of details seems The basophilic and eosinophilic granulocytes of necessary. the blood and tissue remain a puzzle. The fact of their concentration in certain areas of inflanima II. REVIEW OF HOST DEFENSE tion suggests that they have a defensive role, and MECHANISMS yet they are not phagocytic nor are they sources A. G@n@ of antibody. The eosinophil is a major producer of The mechanisms by which a host organism re histamine, and the ba.sophil (or at least the rather acts so as to produce a condition detrimental to similar tissue mast cell) produces both serotonin an invading pathogen and, hence, conducive to the and histamine. These facts, as well as their occur continued survival of the host are of many types. rence in allegeric type hyperimmune reactions, They may be chemical, as so well exemplified in seem adequate evidence that they are in some way antibodies which form chemical union with por involved in host-pathogen interrelationships, al tions of the pathogens; or phy@ica1, as i@ithe fo@ma though the exact mechanism and importance of tioa of dense barriers by the building up of scar these cell types remains obscure. and i@ifiammatory t@issuewhich inhibit the spread of a pathogen into new areas, and by fever which C. NONCELLULARDEFENSE MECHANISMS inhibits an invading pathogen by creating a tem 1. Nonspecific mechanisms.â€”Noncellular fac perature which is unsuitable for continued propa tors are mostly humoral. The usage of this term gation of the pathogen while not detrimental to has evolved through the days of Hippocrates and the host. They may be specific, i.e., directed Galen and Samuel Bulwer, s@that now it is essen against that specific pathogen; or, nonspecific, i.e., tially synonymous with extracellular fluid. From equally effective against a variety of pathogens. the standpoint of laboratory investigation human They may be cellular or humoral, i.e., mediated by factors are serum factors, but the broader term is cells or by noncellular â€œhumors.â€• significant because it recognizes a broader field of distribution and reaction for such factors and the B. CELLULAR DEFENSE MECHANISMS possibility that serum may not provide a sample The polymorphonuclear neutrophilic granulo which is representative of the whole. cytes (â€œpolysâ€•)are the most dramatically defen The nonspecific humoral defense mechanisms sive cell. They can readily be observed to engulf include complement, properdin, certain hormone bacteria and other particulate matter. They ac like factors, and quite probably a whole host of as cumulate in tremendous concentration locally and yet unknown factors. There is no doubt of the par in the blood in response to acute inflammation. ticipation of nonspecific humoral factors in host The tissue macrophages which may be the same as pathogen interactions, but the accomplishment of or closely related to the monocytes of blood and such reactions in terms of host welfare remains lymph nodes are less theatrical but possibly even obscure. The activity of the complement system is more efficient as a defense mechanism, since they most clearly demonstrated in antibody hemolysis. too concentrate in inflammatory areas, engulf de The reaction of antibody with the erythrocytes bris, and stay around to finish the job which the occurs whether complement is present or absent, polys so dramatically initiate. Even the erythro but, if absent, cell destruction does not ensue. It cyte may function indirectly in host defense by is difficult to see how red cell destruction can be a adsorbing onto its surface viruses or bacteria defense mechanism; but this perhaps artificial phe which are thereby rendered more susceptible to nomenon is the easiest to work with in the labora

tory, and the mechanisms involved in hemolysis and more recently Nelson (1@9) has considered it are paralleled by such phenomena as bacterial cell a â€œnaturalantibody.â€• The properdin system (i.e., destruction and virus inactivation which are more properdin plus complement plus the divalent ions), readily acceptable as host defensive reactions. upon reacting with certain viruses (9, 53, @56,86), Complement (40, 105, 15@) is a complex of at bacteria (@0@),and protozoa (48), causes destruc least four and pribably 6 or more (13, %8, 106) tion of the microorganisms, and thus the properdin components which are unromantically kiiown as system merits inclusion in our catalog of host de Cl, C@, CS, C4, etc. They are distinguishedon the fense mechanisms. Excellent reviews of properdin basis of biochemical characteristics such as de have recently been published by Eyquem (45) and struction by ammonia (C'4), adsorption onto by Isliker (8@). zymosan (C'S), and precipitation (C'l) or failure Another nonspecific humoral factor is leuko to precipitate (C's) when dialyzed agthnst water. taxine, described by Menkin (i@O) as a tnaterial C'l is a proesterase (106) and is the component produced in inflammatory tissue, presumably dur which is co@rnbined (fixed) first in the reaction of ing the process of cell necrosis, which has the @omplement with an antigen-antibody complex. capacity of causing leukocytosis, increasing vascu The proenzyme is activated in this process. C'4 lar permeability in the region of the iidlamnÃ¬Ã¡tion, reacts into the complex next, followed by C'@, and and thereby concentrating the leukocytes in the in the process they are said to be irreversibly de inflammatory area. The material has not, to my stroyed by the C'l esterase. Fi'ially, C'S reacts knowledge, been studied by other investigators. into this antigen-antibody-complement complex Other, even less well â€˜understood, factors are (148), and it is only after all the components of known to exist. Kidd discovered a tumor-inhibit complement have reacted that The chÃ¬aracteristic iTkgeffect of guinea pig serum *@hich is neither antigen-antibody-complement reaction (e.g., he properdin nor any of the four recognized compo nÃ¬olysis) is seen. The presence @fmagnesium ions nents of complerne@nt (76, 90). Some human sera is an absthute requirement for these reactions, and contain a heat-labile factor which enhances certain calcium ions are required for maximal reaction. virus-neutralizing antibody reactions. This effect In 1954 further confusion was introduced and is apparently not due to specific antibody or corn further interest was aroused in nonspecific sero plement or properdin (174). logical factors by the discowry of properdin by the The amorphous ground substance of connective late Dr. Louis Pillemer (139, 14@). Properdin, like tissue is an extracellular material, viscous in con the complement components, is a serum protein; sistency and of high polysaccharide content. Its but, unlike complement, properdin is not known importance in the interplay of host and pathogen to participate in any antigen-antibody reaction. It was clearly demonstrated in the studies of Duran does react with a rather wide variety of neutxal Reynals which demonstrated that â€œspreadingfac polysaccharides of microbial, animal, and plant torâ€• (hyaluronidase and perhaps other enzymes origin, int4uding the yeast product â€œzymosanâ€• which diminish the viscosity of connective tissue (14@). Its diseo@crerywas so long delayed because ground substance) enhanced the spread of tumor its separation from C'S depends on incubation causing and other viruses from a subcutaneous with zymosan at 15Â°â€”17Â°C.instead of 37Â°C. inoculation site (39). Properdin is not an antibody in the usual sense of @2.Specific mechanisins.â€”Antibody is serum that word. It is a constantly present serum compo gamma â€˜globulinwhich has been specifically modi nent which is not specific i@nthe choice of polysac fied as a result of the intrusion into the body of a charides with which â€˜itwillreact; nor is its level in foreign material (antigeu)â€”modified in such a way fluenced (except transiently) by tlÃ¬eadministra that it will react specifically with that same foreign tion of polysaceharides. However, the reaction of material and no other. The degree of this specifici properdin with zymosan bears an interesting par ty is extremely fine. It would seem axiomatic that allel to antigen-antibody reactions in that the the determinant of antibody specificity is chemical properdin-zyinosan complex will also fix comple structure, although there is little knowledge con ment components in the same order and with al cerning precisely what changes in globulin struc most the same characteristics as does an antigen ture determine this specificity. There are examples antibody complex. In fact all the known reactions of antibody reacting (cross-reacting) with a mate of properdin necessitate the participation of the rial of completely different source than the stimu four components of complement and mag@Ã¬esium lating antigen. For example, if rabbits are given ions. This resemblance to antigen-antibody reac injections of a suspension of a guinea pig kidney, tions prompted Pillemer to refer to properdin as the resulting antibody will react not only with perhaps â€œaPrimordal type of â€˜antibody'â€• (138); guinea pig kidney but also with sheep erythro

cytes, with mouse brain, and even with some ate reaction but after a delay of @4â€”7@hourscauses strains of pneumococci. These are called hetero a local inflammatory lesion characterized by phile antibody reactions (literature reviewed in edema and infiltration of mononuclear eosino reference 173) and are thought not to violate the philic leukocytes and mast cells. This is known as rule of specificity, but rather to indicate that there the delayed hypersensitivity type of response. are identical antigenic groups in each of these That this host reaction can function as an effective materials of diverse origin. Most known antigens defense mechanism is demonstrated by the pro are protein, but some polysaccharides are anti phylactic value of BCG vaccination against tu genie (7@), and lipides (1.5), nucleic acids (137), berculosis. It seems possible that the mechanisms and even simpler compounds (96, 97) may func are similar to those in sensitivity states charac tion as haptenes, i.e., when administered together terized by serum antibody, but that the anti with a protein they may dictate the limits of bodies are concentrated on or in cells such that no specificity. detectable excess escapes into the circulation. The It seems well established that more than one presence of antibody-like activity on cells has been type of antibody molecule may be produced in re demonstrated by transmitting sensitivity to non sponse to a single antigen, but these differences sensitized individuals by transfer of lymphocytes are very slight (85). For present purposes it is suf or blood leukocytes (97, 103, 154). In histologic ficient to assume that all antibodies produced in appearance, in the absence of detectable circulat response to a single antigen will react only with the ing antibodies, and in transferability through cells, appropriate antigen. Antibody may be detected the delayed hypersensitivity reaction resembles however, by a variety of reactions which vary the immune reaction to tissues such as is seen in greatly in type and sensitivity. Consequently, anti second set tumor transplant. These parallels (104) bodies are often referred to according to the detec suggest the possibility that the mechanisms of re tion technic as if they were of many different jection of transplanted tumors may be the same as types. For example : agglutiins (or agglutinating delayed hypersensitivity mechanisms, and thus the antibodies), precipitins, lysins (or cytolysins, or phenomenon becomes of interest to the oncologist. hemolysins) , opsonins, complement-fixing anti Specific immune tolerance is a paradoxical phe bodies, neutralizing antibodies, protective anti nomenon in which the exposure of a fetal or new bodies, antitoxins, agglutination-inhibiting anti born animal to an antigenic material results in sub bodies. Antibodies circulating in the blood stream sequent acceptance of that particular antigen as if reach almost every part of the body and thus can it were a normal body constituent even though in react with extracellular antigens. The prophylactic actuality it is a foreign and possibly noxious agent and therapeutic effect of specific antibody for (18, 19, 118). Although it may seem paradoxical to many infectious diseases is common knowledge. include such a phenomenon among immune mech In addition to the well known concepts of pas anisms it appears that such reactions obey the sive immunity (conferred by administration of rules of antigenic specificity as seen in more con antiserum) and active immunity (produced in re ventional types of immune phenomena. Most of sponse to administered antigen), the concept of the work with tolerance has concerned skin graft â€œadoptive immunityâ€• has recently been intro ing procedures rather than nonliving antigens or duced. Adoptive immunity is continued produc microorganisms. However, it seems possible that a tion of antibodies by lymphoid cells transplanted mechanism which will allow the acceptance of from an actively immunized donor to a recipient homotranspianted skin as if it were a normal body never directly exposed to that antigen (59, 1@3, constituent might also permit the unopposed per 154). sistence, even propagation, of other tissues or Allergy is characterized by a highly specific host microorganisms if the initial exposure occurred reactivity for certain antigens (allergens), and in during embryonic or neonatal life. It is conceivable many allergic diseases such as hay fever, asthma, that some such phenomenon accounts for the per and serum sickness antibody which reacts' specifi sistence of viruses through successive generations cally with the causative allergen can be demon of individuals, as is known to occur with Rickett strated in the serum. In other allergic states, such siae (34) and several oncogenic viruses (@0, @1,69). as poison ivy sensitivity or tuberculin sensitivity, The phenomenon of tolerance is an area of very circulating antibodies are not demonstrable by active investigation by many laboratories at the present technics, but highly specific tissue sensi present time and should yield interesting results of tivity is demonstrable by skin tests. The tuber basic as well as clinical import in the next few culin test is the prototype. It causes no immedi years.

D. FACTORS INDIRECTLYINFLUENCING Therefore, while it is conceivable that cortisone HOST DEFENSE and possibly other hormones have a direct influ Several other factors which influence incidence, ence upon the susceptibility of cells to damage by time of appearance, or rate of progression of cancer viruses or other noxious agents, it seems more in humans or experimental animals are known. probable that they affect host-pathogen relation They are worthy of mention in the present discus ships through the previously discussed cellular and sion because some or all of them may have these humoral defense mechanisms. effects because they exert influences upon host de 3. Nutrition.â€”Nutrition affects host defense fense mechanisms. It seems probable that none of mechanisms. Many vitamin deficiency states de these is in itself a mechanism of host defense, but crease antibody-forming capacity in experimental rather that the effects are mediated through the animals (8). Serum complement levels are reduced cellular and humoral mechanisms discussed above. in rats with pyridoxine deficiency (8). Vitamin A 1. Heredity.â€”Genetic factors clearly influence deficiency diminishes resistance to infections due susceptibility to infection and to other toxic to epithelial changes (17). Vitamin antagonists or agents. The classical experiments of Webster (9204) restricted diets which bring about deficiency by which the PRI (Princeton Rockefeller Insti states of folic acid (190), pyridoxine (1921),or ribo tute) resistant and susceptible lines of mice were flavin (187) inhibit growth of various mouse tu bred by selection from a common stock illustrate mors. Dietary restriction is said to decrease fre the importance of genetics in resistance to bac quency and retard time of onset of spontaneous terial and viral disease. It is common knowledge tumors in mice (131). In experimental animals, that various inbred lines of mice have different protein depletion may diminish the rate of growth susceptibility to oncogenic viruses such as Bitt of transplantable tumors but does not prevent the ncr's milk factor, Gross' leukemia, and Friend's progressive course (193). Folic acid antagonists are leukemia. In clinical medicine, various racial therapeutically useful in the chemotherapy of groups have marked differences in incidence of cer acute leukemia in man. No causal relationship of tam types of cancer, even when living in the same diet to the spontaneous occurrence of tumors in geographic area (143, 186, 92192).While such differ man or animals has been recognized, but the pos ences in racial incidence of cancer may result from sibility that nutritional factors may be related to cultural factors influencing exposure to carcino differences in cancer incidence patterns in differ genic substances, genetically determined differ ent geographical, racial, or religious groups cannot ences in susceptibility have not been excluded. be exluded. Genetic studies of cancer in human families sug 4. Age.â€”The age of a mother at the time of gests that genetic as well as environmental factors parturition may influence cancer susceptibility of influence cancer risk (1392, 9200). The genetic make the offspring. Strong (189) presented data indicat up of an individual cannot, of course, be altered, ing a decreased susceptibility to chemically in and hence this factor appears to have little bearing duced sarcomas in mice born in late litters. Law on the problem of cancer therapy or prophylaxis (1092) reported that frequency of spontaneous leu in man. kemia was lower and time of onset later in mice 92. Hornwnes.â€”Hormones are also known to born of old mothers. No study relating human play a role in host resistance. The most obvious cancer to maternal age has yet been published. example is the greater propagation and pathoge The incidence of acute leukemia is increased in nicity of certain bacteria and viruses in a variety children with mongolism (95), and the frequency of experimental animals after intensive treatment of mongolism increases directly with age of the with adrenocortical steroids or adrenocortico mother at time of delivery (136), but it does not tropin (ACTH) (195). Agosin et at. reported that necessarily follow that there is any causal relation cortisone treatment induced metastases of a trans ship between maternal age and leukemia. If any planted mouse tumor (92). It is known that the such relationship does exist in man these observa adrenal steroids and ACTH cause depression of tions suggest that it might be the reverse of that lymphocytes and eosinophils (73), inhibit anti reported for mice. body formation (134) and phagocytosis (150), and III. ANTIGENIC ANALYSIS retard healing of wounds (147) and abscesses (181). Cortisone has no apparent effect upon the In basic research, antibody technics provide rate of growth of Bunyamwera virus or cyto poorly understood but extremely sensitive tools for pathogenesis in human fibroblast tissue cultures the detection of biochemical differences. If differ where no defense mechanisms are operative.' 1Unpublishedstudies from this laboratory.

ences between normal and neoplastic cells were labeled (145, 9207) and the fluorescein-labeled (78, detected by these technics, the exploitation of such 130, 9205)antibody technics are not more discrimi differences to achieve specific antineoplastic ef nating in an immunologic sense but offer previous fects would be attempted by all available meth ly unavailable accuracy in the anatomical localiza ods. Such methods would include but would not be tion of antigens in tissues and cells. Zilber (9218) limited to specific immune mechanisms. It is con reported on use of the phenomenon of immuno ceivable, for example, that antigenic analysis logical tolerance to render an experimental animal might reveal differences in polysaccharide, amino nonresponsive to normal tissue antigens but still acid, or nucleic acid haptenes against which spe capable of producing antibodies to abnormal can cific antimetabolites might be prepared. cer antigens. This ingenious approach for difleren Antigenic analysis is an old approach to cancer tiation of closely associated antigens deserves fur researchâ€”a much traveled path liberally littered ther study but will probably prove difficult of with a voluminous literature. The older work can application. In this laboratory it has been very dif be brusquely evaluated as revealing no qualitative ficult to induce tolerance to heterologous tissues. and no consistent quantitative differences between Tissue cultures were used for detection of cyto cancer tissue and comparable normal control tissue toxic antibodies as early as 19927 (110), but this (11, 71, 1892,9210,9217). The problems in antigenic approach became practicable only with the advent analysis of tissues are great and are readily ap of stable cell lines (58, 117, 19292,1692).This technic parent. Cancer tissue is a mixture of cancer cells, offers the advantage of a single cell type, thus re normal cells, and noncellular constituents. The ducing somewhat the complexity of antigens to be choice of a normal tissue as a control for tumor is expected in whole tissue preparations. Salk (1692) difficult if not impossible because of marked differ introduced the time-saving modification of in ences between normal and neoplastic tissues in ab direct detection of cytopathology through pH dif solute concentration and relative proportion of ferences instead of microscopic examination. each of these constituents. Even within a single Zilber (9216) has also used anaphylaxis in guinea cancer cell there are normal constituents which pigs after desensitization to normal tissues as a may obscure the cancer antigen in both in vitro means of detecting specific cancer antigens, and tests and when used for antiserum production. others (30, 63, 1192)have used the basically similar Current renewal of interest in this area derives Schulz-Dale technic. Takeda (1992) has utilized from the development of technics which may cir rate of rejection of repeat (â€œsecondsetâ€•)hetero cumvent these difficulties. transplants to study antigenic relationships be tween various tumor lines. Theoretically these last A. METHODS OF ANTIGENIC ANALYSIS three technics, based on the active immune status 1. Immunologic technic@.â€”One approach is the of an experimental host, should not be more dis use of new, more sensitive, and more discriminat criminating than previously used methods; but ing technics for the detection of antigens and anti final evaluation awaits further studies. bodies. The adsorption of antitumor antisera with 92. Purification of antigens.â€”A second approach normal tissues to remove antinormal components is the better separation of cancer antigens from of the antiserum is a relatively recent concept normal antigens prior to injection into animals for which is now used almost routinely. Using this antibody production, or prior to use in tests in technic and standard complement-fixation meth vitro. Rapport and Graf (149) have extracted a ods Korosteleva (93) reported that specific cancer nonphosphorus-containing lipide (sphigmo lipide) antigens were demonstrable in human tumors and which appears to be a haptene in that it does not that the same cancer-specific antigen was some react as an antigen by itself but does exhibit anti times demonstrable in tumors of different individ genie specificity when mixed with other lipides and uals, but that there was no cancer antigen common protein in a complement-fixation test. These to all human cancers. The extremely sensitive studies are not yet sufficiently advanced to permit hemagglutination technic of Boyden (925)utilizes final evaluation of qualitative specificity or the antigens adsorbed onto tannic acid-treated eryth degree of cross-reaction between various normal rocytes to make visible antigen-antibody reactions and tumor tissues, but the normal tissues studied which are often undetectable by older methods. thus far contained little or none of the â€œcytolipin The Ouchterlony technic (9292,70,992) separates and Hâ€•found in several types of human cancer. Re identifies antigens on the basis of differential dif cent studies from Japan report isolation of a phos fusion through an agar gel. An electrophoretic sep phorus-contaiing lipide haptene from cancer tis aration of antigens is accomplished by the gel sue, but detailed data are not yet available (94). electrophoresis technic (9215). The radioiodine A phospholipide haptene has also been demon

strated in human cancer by Bjorklund and co proach is illustrated by the studies with the EL4 workers (923). Another approach is the use of and EL5 mouse leukemias (60), which indicate fluorocarbons as introduced by Gessler (55) to con that the leukemic cells contain antigens which are centrate antigenic materials from crude tissue sus not present in normal tissues of the host (CS7BL pensions (194). Chemical methods of separating mice) but which are common to the two lines of and concentrating anticancer antibodies from a leukemia. Contrariwise, studies of this type by complex antiserum have also been developed (36). Sachs and Feldman (161) with several tumors of The use of newer physical methods for fractiona C3H and DBA mice failed to reveal any antigens tion of cancer tissue antigens is illustrated by the in tumor which were not also present in normal studies of Toolan (198), who separated the trans tissues of the isologous line. In fact, their studies plantable human epidermoid carcinoma #3 (H.Ep. indicate that some tumors lack some of the anti #3) into five subcellular fractions by differential gens which are present in the normal tissues of sedimentation technics. Her results indicate a high their hosts. The studies of Hirsch et at. (79) using degree of antigenicity in the â€œfluffylayer,â€• which low passage tumors of inbred mice also suggest appears to consist principally of endocytopla.smic that tumors may contain antigens foreign to their reticulum (ergastoplasm). Similar studies with isologous host. For the study of human cancer this mouse tumors (38, 113) also revealed antigenic approach is possible only through the cooperation activity in cytoplasmic factors. These observations of human volunteers. In such studies (175) it has point to cytoplasmic rather than nuclear constitu been found that there is cross-antigenicity between ents as a likely site in which to look for antigenic the few human cancer cell lines which have been components characteristic of the neoplastic cell. studied, and the very limited studies of normal The fact that these fractions are thought to have cells showed no evidence of common antigens be a high lipoprotein and low nucleic acid content is tween normal (fibroblast) and neoplastic (epider of particular interest in view of the lipide antigens moid) cell lines. These studies are not sufficiently obtained by chemical separation technic. extensive or intensive to permit uncritical accept Bjorklund (9292)has suggested and applied the ance, but the results to date are consistent with interesting concept that if cancer tissues contain the hypothesis that there may be unique cancer cancer-specific antigens in common, such antigens antigensâ€”even in human cancerâ€”and that such would not be diluted in a tissue pool, whereas anti antigens may be common to cancer of different gens unique to individuals would be diluted in pro individuals. portion to the number of individuals represented in the pool. Thus, if the basic concept is correct, a IV. ARE THERE HOST DEFENSES pool of many human cancers would in effect ac AGAINST CANCER? complish a selective concentration of cancer-spe The most basic problem upon which rests all cific antigens. hope for clinical applications of immunological The development of mass tissue culture tech methods is whether host defense mechanisms nics and the development of twenty or more hu against cancer actually exist. As yet there is no man cell lines which can be grown in continuous answer to this question, but both clinical and ex passage promise to solve the problem of mixed tis perimental observations seem to indicate that man sue by providing a cell mass consisting of a single may indeed have mechanisms by which he resists cell type. Exploration of this source of tissue for neoplastic disease. immunological studies has barely been initiated because of production problems and difficulty of A. CLINICAL OBSERVATIONSSUGGESTIVEOF HOST obtaining adequate normal cell cultures for con DEFENSES AGAINST CANCER trols. There is marked variation in the clinical behav 3. Choice of experimental host.â€”Another meth ior of cancer even within a single histopathologic od of improving antigenic analysis studies is better type and within groups of patients which are ap experimental control of the host in which anti parently homogeneous as to sex, age, and race. bodies are produced. The use of the same species There is frequently a lack of correlation between for the source of both antigens and antibodies the clinical course of cancer and the estimated simplifies antigenic analysis because it eliminates â€œgradeof malignancyâ€• as judged by histopatho reactions to all those antigens which are common logic criteria. Some cancers have a prolonged pre to all the individuals of a species. Even within a clinical stage. This was documented for lung can species, the complexity of reactions can be further cer by Rigler's (153) retrospective study which re reduced by the use of animals which are genetical vealed identifiable lesions as long asS years before ly (and hence antigenically) very similar. This ap clinically apparent disease. A similar situation for

cancer of the prostate is indicated by the fact that that some tumors do show parallel growth poten it is at least 4 and possibly 10 times more frequent tials in original hosts and on transplantation, as at autopsy than is apparent from clinical evidences illustrated by Toolan's H.Ep. #3 tumor [196] and of the disease (80). Cancer metastases (thyroid and by the extensive studies of Greene [67]). If, how breast cancer are good examples) may lie dormant ever, the relative growth capacity of a series of or latent for years and even decades before exhib transplanted cancers does not parallel their growth iting a growth spurt with resulting clinical disease. characteristics in their original hosts, it is clear In SitU carcinoma of the cervix may apparently that factors other than innate capacity for repro undergo spontaneous regression as judged by dis duction must be operative and that these factors appearance of histologically proved lesions (9214). must either be resident in the host or must have Spontaneous remissions will occasionally occur arisen after explantation. even in widely disseminated cancer (7, 43, 5%, 88, The administration of neutral polysaccharides 151, 185). Recent cytologic studies have indicated of diverse plant, animal, and microbial origins to that cancer cells are present in blood (492,144, 163, experimental animals profoundly affects resistance 165), lymph (9203), pleural and peritoneal fluids2 to bacterial infection and growth of tumor trans (183) and in operative wounds2 (168) much more plants. Large doses of zymosan (a crude poly frequently than the subsequent development of saccharide from yeast) or bacterial polysaccha metastases would indicate, indicating that not all rides transiently decreases resistance of mice to loose cancer cells are capable of establishing a gram-negative bacterial infections (140, 160) and metastatic lesion. causes increased growth and lethality of Sarcoma Occasional cancers are accompanied by a 180 in mice (927),human epidermoid carcinoma #3 marked inflammatory infiltrate, for example in in in rats (135), and a human intestinal adenocarci flammatory carcinoma of the breast and occasion noma in rats (74). Conversely small doses of poly ally in prostate carcinoma. This is a local host re saccharides increase resistance of mice to infec action to the presence of tumor which might be tion (81, 98, 99, 100, 156, 160) and increase rejec interpreted as defensive. Berg (16) presented evi tion of Sarcoma 180 (926,927)and Sarcoma 37 (114) dence that in human breast cancer the presence of in mice, Yoshida sarcoma in rats (91), and human a plasma-cell reaction is prognostic of a favorable sarcoma #1 in conditioned 3That these effects clinical course. Lymphoid (184) or eosinophilic are the result of depression and stimulation, re (9213) infiltrations are stated to be favorable prog spectively, of nonspecific host defense mechanisms nostic signs in gastric cancer. is indicated by the lack of cross-antigenicity be Grace and Dan (61) reported that skin tests tween zymosan and these pathogens. It is also with antigen prepared from their own tumor tissue apparent from dosage factors that this is not a produced wheal formation in patients with in direct effect of the zymosan upon the tumor. The flammatory breast cancer (indicative of serum effect of polysaccharides on susceptibility to infec antibodies) but not in patients with noninflaninia tion and tumor growth varies inversely as its ef tory cancer. Graham and Graham (65) reported feet upon serum properdin levels (926,98, 99, 141), that complement-fixing antibody against their suggesting the possibility that properdin or some own tumor antigens was demonstrable in serum of other defense mechanisms which fluctuate in par patients with gynecological cancers of favorable allel with properdin may be directly involved in prognosis. the tumor rejection mechanism. Kidd has demonstrated in guinea pig serum a B. EXPERIMENTAL STUDIES SUGGESTIVEOF HOST nonspecific humoral factor which inhibits the DEFENSES AGAINST CANCER growth of a rat lymphosarcoma (90). This work, The growth of a human neoplasm when trans which has recently been confirmed (3,76), suggests planted to experimental animals or human volun participation of humoral factors other than teers does not always parallel its aggressiveness in properdin or complement in tumor rejection. the original patient. Toolan's human sarcoma #1 In recent studies with established lines of hu (H.S. #1) grows rapidly in conditioned rats and man cancer cells4 (176), homotransplants in hamsters and in chick embryos, whereas it was a healthy recipients elicited an acute inflammatory circumscribed lesion in the patient and has not reaction and were promptly rejected after a brief recurred 6 years after local excision (35, 196, 197). Conversely, most highly malignant human tu â€˜M.Aizawa and J. Palm, personal communication. mors have not been transplantable at all in a C. M. Southam, A. E. Moore, C. A. Doan, R. H. Brooks, heterologous host. (This does not deny the fact A. G. James, and C. P. Rhoads, Homotransplantation of human cancer and normal cell lines into normal and cancer 2 S. H. Seal, personal communication, July 31, 1959. patient volunteers (in preparation).

period of propagation, as would be expected. In accomplished many times, but most of this work contrast, the same type of transplants in patients has no carry-over to the problem of human cancer, with advanced cancer did not elicit an inflamma because heterologous or homologous cancer trans tory reaction and continued to propagate for 4â€”6 plants are obviously foreign to and hence antigenie weeks and often longer before rejection started. in the recipient. The possibility of inducing specific When rejection did occur, the cellular response was active immunity against the development of spon of the mononuclear type. Apparent delay of rejec taneous cancer in man demands that there exist tion of direct homotransplants of human cancer unique human cancer antigens. These might reside tissue (rather than established human cell lines) in the neoplastic tissue or in the oncogenie agent and of human adult or embryonic skin has also which might or might not persist within the cancer been reported by Grace (63) and by Snyderman which it induces. It further demands that the num (170). These observations are interpreted as mdi ber of these hypothetical cancer antigens be suffi eating that the patient with advanced neoplastie ciently small so that immunization of a population disease is deficient in certain mechanisms by which against a manageable number of these antigens homotransplanted tissues are rejected. The postu would provide immunity against the development lated defect does not appear to be in ability to pro of a considerable proportion of possible antigenic duce circulating antibodies or to mobilize a leuko types of cancer. These unique antigens would not eyte reaction (176). Collateral studies indicate that necessarily be protein nor complete antigens. The these same patients have a deficiency of serum possibility exists that haptenes which are unique properdin (178), but there is no evidence that the to cancer could be made antigenie by combining properdin deficiency is the cause of the defective them with suitable carrier antigens. One exciting rejection response. aspect of the virus theory of cancer etiology is its None of these experimental studies proves that implication for specific immune prophylaxis. It is there is host resistance to spontaneous cancer, be clear that if a finite number of viruses were the cause each deals with transplanted rather than causative agents for any considerable proportion spontaneous cancer, and it must not be assumed, of human cancer, then these viruses would satisfy although the hypothesis is worthy of considera the requirements for specific cancer antigens. Lest, tion, that the same mechanisms which participate however, there should be any over-optimism in in in the rejection of transplanted tumors can also terpretation of this suggestion, it should be re restrain spontaneous neoplasms. called that to attempt immunization against a In spite of the complete absence of proof, the large number of specific cancer antigens would be existence of so many suggestive bits of clinical and analogous to attempting simultaneous immuniza experimental data sustains the working hypothesis tion against a wide variety of infectious diseases. that cancer is not a wholly autonomous growth but A final note of pessimism is impelled by the knowl may be susceptible to restraint by host mecha edge that, if active immunization against sponta nisms. neous cancer is achieved at the laboratory level, the clinical field trials which would be necessary V. IMPLICATIONS OF IMMUNOLOGY to establish its validity in the general population FOR CLINICAL ONCOLOGY might well require more than two decades of ob The implications of immunology for problems servation to permit adequate evaluation. There of clinical cancer are many and are intriguing. At has apparently been little research work aimed present, however, they are theoretical at best and directly at this approach to the cancer problem, often purely speculative. Under the headings of although such studies could be undertaken in ex prevention, detection, prognosis, and treatment perimental animals such as mice which develop we will consider first theoretical aspects and then spontaneous cancer. The cancer homotransplanta experimental studies at laboratory and clinical tion studies performed at the Ohio State Peni levels. tentiary4 (175, 176), although not designed with this objective in mind, will be evaluated from this A. CANCERPREVENTIONâ€”THEORETICAL standpoint by comparing the eventual cancer in CONSIDERATIONS cidence in men who have been inoculated with a The possible implications of immunology for variety of human cancer cells and in a parallel cancer prevention reside in the possibilities of in group of paired controls. creasing the efficacy of postulated nonspecific de fense mechanisms, or inducing specific active im B. CANCER DETECTION munity. Active immunization against transplant The application of immunologic methods to able tumors in experimental animals has been cancer detection is theoretically possible (a) by the

detection of cancer-specific antibody in serum, Schulz-Dale technic used for detection of the anti (b) by the detection of cancer-specific immune re gen-antibody reaction. They reported data inter actions of tissue (e.g., skin tests), or conversely preted as indicating circulating cancer antigens or (c)bythedemonstrationofcancer-specificantigen haptenes in a very high percentage of cancer pa or haptene in a readily sampled material such as tients and rarely in patients without cancer. The serum or urine, and finally (d) by the detection specificity and sensitivity of these technics for through immunologic technics of changes in body cancer, and its possible use for cancer detection, composition or reactivity which indirectly indicate cannot yet be evaluated but certainly merit fur the presence of cancer. Many past and present in ther investigation. vestigations fall into these categories. 4. Indirect immunologic technics.â€”The fourth 1. Serum antibody.â€”Sporadic attempts have approach has likewise failed to yield any test for been made to demonstrate cancer antibodies in the cancer detection, but is illustrated by studies of serum of cancer patients, with the use of various Kahn's â€œuniversal serological reactionâ€• (109), crude preparations of human cancer tissue as heterophile reactions (173), trichina precipitins antigen. Reports concerning the detection and (180), C-reactive protein (64, 9211),and Abderhal significance of such reactions have been presented den reaction (89), and the current studies of serum with various degrees of enthusiasm but quite uni properdin (t@ideinfra). formly without conviction (see bibliography in An admission of pessimism seems appropriate, reference 66). because a cancer test which is based on immunolog A clinically useful test would require a widely ic (or chemical) methods will be positive only if the distributed cancer antigen, specificity of the re cancer is liberating something into or removing action for cancer, and a high degree of sensitivity. somethingfrom extracellular fluid in quantities suf The prospects for such a test seem discouraging at ficient to yield a detectable abnormality. It seems present, but studies using more purified antigens unlikely that this would occur sufficiently early in or more discriminating serological reactions (as the course of disease in most people to permit de discussed under â€œantigenic analysisâ€•) will con tection in time for effective treatment. However, tinue to be of interest. the need for better cancer detection methods is so 92. Skin teste.â€”Skin tests for cancer diagnosis by great that studies in this direction certainly will detection of sensitivity to cancer antigens have and should continue. not been investigated to the knowledge of this writer. The skin testing technic presents the same C. PROGNOSTICTESTSIN CANCER problems of antigenic specificity as do in vitro It is somewhat easier to conceive of useful im technics and has as disadvantages the necessity of munologic methods for cancer prognosis, for the patient participation and the possibility of detri very reason that they seem unlikely for cancer de mental reactions. It does, however, offer the possi tection. As cancer grows, no matter how inacces bility of detecting tissue-fixed antibody through sible its location, it would be expected to liberate the delayed hypersensitivity type of reaction, which or to remove various materials which might be is usually unaccompanied by detectable serum immunologically detectable in direct proportion to antibodies. the total cancer mass, and thus the fact of demon 3. Circulating antigens.â€”Since a search for anti strability and the degree of such changes would bodiesâ€”whether in serum or tissueâ€”presupposes roughly correlate with prognosisâ€”i.e., they would that the cancer patient has been exposed to cancer correlate with prognosis to the same extent that antigens and has reacted with development of cancer mass correlates with prognosis, which is not specific antibodies, it might be supposed that this necessarily close. Studies of serum properdin approach is doomed to failure, since such a test levels' (44, 47, 1927, 157, 159, 178) suggest such a would necessarily fail to detect those patients who correlation, but the data are not yet sufficient for do not produce an adequate antibody response to one to hazard a guess concerning the possible prog their developing cancer. It seems logical, then, to nostic importance of properdin determinations in attempt to detect a cancer-specific antigen which cancer patients. might be released from the cryptic cancer into serum or other body fluid. This approach was at D. IMMUNOLOGIC APPROACHES TO THE tempted with suggestive results by Mann and TREATMENT OF CANCEI@ Welker (115) by a precipitin technic and a rabbit 1. By specific immunologic mechanisln3.â€”The antihuman cancer serum. Makari (1192) and Bur utilization of specific immune mechanisms for can rows (30) have recently reported on this same type cer treatment rests on the possibility that there of study, with the sensitive but cumbersome may be a unique cancer antigenâ€”otherwise, spe

cific immune mechanisms would react detrimen lus by the same cancer antigen. It must be postu tally against normal as well as tumor cells. It is lated that either the original stimulus of a develop also necessary that every individual's cancer be ing cancer was quantitatively inadequate to excite not unique, but rather that cancer fall into a finite an effective response, or that the patient's immune number of antigenic groups, comparable to the mechanisms were temporarily inadequate and sub causative agents of infectious disease. A third sequently overwhelmed by the mass of antigen. necessity is that the unique cancer antigen persists To remove cancer tissue and reinject it into the in or on every cancer cell throughout the course same individual either in its original state or after of the disease. If some human cancer were found manipulation designed to concentrate the antigen to be caused by a virus and if a specific antibody would thus seem to be illogical. It might be argued, against that virus could be prepared, it would not however, that the presumed cancer antigen of be effective if (as has been suggested) the virus tumor tissue is not in a form which is an effective disappeared after the neoplastic transformation antigenic stimulus and that purification, concen had occurred, or if the virus reverted to an incom tration, or combination of such antigen with ad plete form such as nucleic acid which was in juvant materials might produce a more effective capable of reacting with antibodies. Still another antigen than is provided by the native tumor tis problem is the possibility that the hypothetical sue. It is also conceivable that serum antibodies are unique cancer antigen against which the antibody produced by a patient in response to cancer growth must act is situated intracellularly, and thus may but are absorbed onto an excess of antigen (tumor be inaccessible to the action of antibodies. There cells) so rapidly that an effective concentration has been no clear demonstration of effective pene capable of affecting all tumor simultaneously is tration of serum antibodies into a cell. The evi never achieved. The often discussed but seldom dence from infectious diseases fits this pessimistic documented observations of regression of metas assumption. Administration of antiserum is thera tases after surgical removal or irradiation of a peutically effective when the pathogenic antigen large primary lesion might be explained by such a is extracellularâ€”as occurs in many diseases due to mechanism.5 This hypothesis suggests the possi bacteria or bacterial exotoxins ; but if the pathogen bility of harvesting serum from the cancer patient is intracellular, as in virus infections, a specific who has been given a maximal antigenic stimulus antiserum is generally ineffective. This inability of and concentrating the antibodies therefrom for circulating antigen to eliminate intracellular virus subsequent therapeutic administration. Investi 18 illustrated in clinical experience by recurrent gations along the above lines have been reported5 herpes simplex, and in the laboratory by the ob (692,68, 65, 66, 87, 188) but give little encourage servation, according to the fluorescein-labeled an ment for immediate clinical applications. tibody technic, that West Nile virus may persist Passive immunization calls for the production (and presumably propagate) within cancer cells for of antibody to cancer antigens in a recipient (the weeks after circulating antibodies have appeared â€œserumdonorâ€•) other than the cancer patient, (177). with subsequent administration to the patient of The approaches to cancer treatment by specific the antiserum so produced. The production prob immune mechanisms might be by active or passive lems in such an approach are many. In theory, the immunization. Active immunization attempts best approach would be the production of a tailor would require inoculation of the patient with made antiserum for each patient. The alternative material containing the unique cancer antigen. is a multivalent antiserum produced against The source of such an antigen presents little prob mixed antigens from many different tumors. By lem in the patient who already has neopiastic dis either method, the serum would contain anti ease because his own cancer tissue would presuma bodies to normal tissues as well as the desired anti bly contain the cancer antigen and the normal tis cancer antibodies, unless it were possible to isolate sue components within the cancer tissue would not the cancer antigen before immunization of the be antigenic in the same individual. However, the serum donor or to selectively remove the antinor theoretical objections are formidable. ma! antibodies before administration of the anti.@ To consider therapy of the cancer patient serum to the patient The tremendous mass of through active immunization demands the unlike cancer tissue which an adinini.stered antibody ly assumption that a patient who has cancer (and would have to affect in the patient with advanced who therefore is already exposed to a maximal an cancer is also a point of great discouragement, but tigenic stimulus and has failed to produce an effec this objection would not be pertinent if serum tive specific ixamune response) nevertheless still â€˜J.W.Pinney, B. G. Byers, and R. H. Wilson,Studies in has the capacity of responding to a further stimu tumor auto-immunity (in press).

treatment could be used in an early stage of can antibodies such as those reacting against the blood cer, as would be logical if an effective agent were group substances, and the term â€œhomologousanti available. The serum donor would presumably be bodiesâ€•has sometimes been used in studies within an animal such as horse, sheep, or rabbit, and thus an isologous system. the patient's treatment would be limited by sensi When an animal is exposed to heterologous tis tization to the heterologous serum protein. The sues, whether alive or dead, neoplastic or normal, latter problem could be minimized by production specific immune mechanisms come into play which of the antiserum in humans, but even if such a subsequently render that animal specifically reac procedure were justifiable on an experimental tive to the antigens in the injected tissue and basis the probability of producing an effective usually result in the appearance of antibodies in antiserum seems poor because serum antibodies the circulating blood. The study of experimental have usually not been detectable in recipients of tumors by this approach has produced a very volu homologous tissue antigens. Sumner and Foraker minous literature which has been periodically and (191)reportedregressionofmelanomainapatient adequately reviewed (11, 71, 1892, 9210, 9217). The given whole blood transfusions from a donor who continued interest in the serologic response to had experienced spontaneous remission of melano heterotransplanted tumors is evidenced by recent ma. If this was truly a cause-and-effect relation publications involving the use of fractionated tu ship it may represent a therapeutic effect of serum mor tissues (38, 194, 198), established lines of hu antibody or cell-fixed antibody against melanoma. man cancer cells (78, 117, 19292,198), and improved The experimental data concerning antibody re methods of antibody purification (36, 145). It has spouse to tissue antigens and the effect of active been repeatedly demonstrated that antitumor sera immunity or antibody administration on the thus prepared in heterologous hosts will inhibit growth of tumors are voluminous, perplexing, and growth of that tumor in vitro or if administered apparently conflicting. In considering this type of prophylactically to an animal just before implan investigation, it is imperative to keep in mind the tation of the same type of tumor. Therapeutic re relationship between the transplanted tissue and sults are also reported in some studies if treatment the recipient. This relationship is termed heterolo is started within 924hours after tumor implanta gous when tissues of one species are transferred to tion. Of recent interest is the demonstration of a recipient of a different species. It is homologous such an antitumor effect with rabbit antiserum when donor and recipient are genetically different against the human carcinoma cell line HeLa grow individuals but of the same species. It is Â£rologous ing in conditioned rats (117). Such studies, how when donor and recipient are genetically identical ever, have no direct implications for human can (at least phenotypically identical). This situation cer, because the test tumor is transplanted in a exists in identical twins and theoretically in closely host in which it is not completely compatible and inbred strains of mice. It is autologous when a tis hence is subject to host defense mechanisms sue is transplanted from one location to another in (whetherhomologousaswiththe animaltumors the same individual. The term isologous is extend or heterologous as in the HeLa cell experiments). ed to include the relationship between individuals Furthermore, in this situation the antiserum may who are phenotypically but not genotypically be directed against normal components of the identical. Thus, F1 hybrids (progeny of a female of transplanted tumor rather than against an antigen one inbred line and a male of another inbred line) unique to the neoplasm. The validity of this last are histocompatible with both parent lines. Trans criticism is supported by studies with Rous sarco plantations from either parent line to such hy ma in which it has been demonstrated that anti brids, or among such F1 hybrids, are therefore con serum against normal chicken tissues neutralizes sidered isologous even though the recipient may purified Rous sarcoma virus preparations (192). carry recessive genes of histo-incompatibility. In When an experimental animal is exposed to a truly isologous system reactions would be the homologous tumors, specific immunity is regularly same as in an autologous system, but it is difficult, produced as evidenced by failure of growth or ac if not impossible, to eliminate all genetic variations celerated rejection of subsequent implants of the which might influence antigenic composition. In same tumor (37, 107, 116). Antibodies may (60) or referring to antibody which is formed to tissue an may not (111) be detectable in the serum of ani tigens, it seems best to use fully descriptive terms mals immunized against homologous recipients. such as â€œantibodyto isologous cells,â€•etc., because Immune responses to homologous normal tissues the term isoantibody, which would be a logical are also well documented. The â€œsecondsetâ€•reac parallel to isotransplantation, is established in tion to a second homograft of skin and sensitiza serological literature to mean naturally occurring tion of Rh-negative recipients by administration

of Rh-positive blood are well known examples in isologous system would have implications for clini clinical medicine. Demyelating encephalomyelitis cal cancer therapy, because such a response would (83), peripheral neuritis (9201),testicular degenera indicate that even if the antiserum did cross-react tion (54), nephrosis (77), nephritis (166), sym with normal cells, an acceptable therapeutic ratio pathetic ophthalmia (392), thyroiditis (9208, 9209), between toxic and therapeutic effects had been hepatitis (14), and adrenalitis (33) have been pro achieved. Many studies (6, 49, 57, 68, 111, 116, duced in various experimental animals by repeated 1924, 146) have demonstrated antitumor immune injections of the corresponding homologous tissue reactions in presumably isologous systems, but or an antiserum against such tissue. The pathology others have failed to do so (10, 107) ; the painstak is attributed to the reaction of anti-tissue anti ing genetic studies of histocompatibility genetics bodies with antigen in the affected tissue. In these by Snell (169) and by Amos and Corer (5) and studies, utilizing â€œvaccinesâ€•ofhomologous normal their co-workers throw doubt on the genetic uni tissues, it has rarely been possible to demonstrate formity of tumor and host in the earlier studies. circulating anti-tissue antibodies, but it must be Recently, Amos and Day (4) were unable to dem emphasized that the serological technics used for onstrate antibody formation against ETA and detection of such antibodies may be completely ELS leukosis in histocompatible CS7BL mice, and inadequate. Foley (50) could not produce immunity to early Antibody produced against a homologous tu passage mammary cancer in C311 mice. On the mor may be prophylactic and sometimes therapeu other hand, Foley (51) was able to produce immu tic when administered to other animals bearing nity in CSH mice against a methylcholanthrene transplants of the same homologous tumor (60), induced sarcoma, only one passage removed from but these studies are subject to all the criticisms its original host, and Hirsch et al. (79) induced a mentioned for heterologous systems, since even in weakly protective active immunity against an a homologous host the transplanted tumor is for early passage mammary tumor in BALB mice. eign to its host and with few exceptions is sponta Thus, there is still no agreement, and no complete neously rejected. No experimental animal studies ly convincing evidence, concerning a specific im are reported in which a homologous animal was mune reaction against a tumor in a truly isologous used to produce serum for treatment of a sponta system; but the possibility still remains that at neous neoplasm. least some tumors show sufficient antigenic differ Ilomotransplantation of human cancer cell lines ences from their host of origin to excite some dc also produces an immune state as evidenced by gree of specific immune response. Also in support accelerated rejection of repeat implants (175). To of this possibility are the observations of Corer date there is no convincing evidence of circulating and Amos (60), who were able to produce anti antibodies in the recipients of such homotrans bodies against the ETA leukosis by inoculation plants. No attempt has ever been recorded of use into the homologous mice and to separate from of serum from recipients of homotransplants as a this antiserum an antibody which reacts with the therapeutic procedure for human cancer, and fail tumor cells but not with normal tissue cells of the ure to detect circulating antibodies in the above C57BL line. Amos and Day (4) extended this type experiments offers no incentive to attempt such of study to three additional in-line tumors with studies. similar results. Of greatest importance from the standpoint of Since a specific immune response necessitates a possible therapeutic applications of immunology recognizably foreign antigenic stimulus, it would to cancer are the studies with isologous systems. seem axiomatic that no normal tissue could be Corer has recently reviewed studies of this type antigenic to the individual of which it is a part, (59). In a truly isologous system those normal unless some change has occurred within a tissue antigens which are present in cancer cells are not which alters its antigenic status with respect to the foreign to the host, and thus any antibody re host. Such changes might theoretically occur sponse would be the result of antigens which are through changes in anatomical relationships, unique to the cancer cells; and the isologous tumor through mutation, or through the acquisition of is in the identical immunological situation with an extrinsic component such as a haptenic chemi relation to its host as is a spontaneous tumor and cal or a virus. An impressive amount of data is ac hence should respond to antiserum treatment in cumulating to support the thesis that certain dis the same way as a spontaneous tumor (ignoring eases of man are due to auto-immunization. such factors as tumor site and vascularization). Studies of Hashimoto's struma have demonstrated Thus, any therapeutic response to antiserum treat circulating antibodies capable of reacting with ment which might be demonstrated in a truly thyroglobulin in vitro (155) and with thyroid tissue

as demonstrated by the fluorescein-labeled anti discourage continued trials of crude antisera but body technic (9206). It may be postulated that in do not constitute evidence against the theoretical this disease some extrinsic pathogen such as a possibility that this approach might yet be devel virus invades thyroid tissue and initiates cell dc oped to the point of practical application through struction with release of thyroglobulin which is improved technics of antigen preparation or anti antigenic and thus produces antibodies only co body extraction. incidently. An alternative hypothesis, however, is The studies of the past and present decade on that the antibodies against thyroglobulin, having reticulo-cytotoxic serum (924, 167) and on krebio been produced, then have the capacity to de zen (1) bear a superficial resemblance to this ap stroy those cells which are rich in thyroglobulin, proach, but since these are prepared from serum o@ thus causing the thyroiditis. Although neither pos animals injected with human spleen tissue and sibility bears immediately upon the cancer prob Actinomyces bovis, respectively, there is no basis 1cm, both are of interest, because the former for considering these materials as anticancer sera. would illustrate that antigens specific for a single The possibility that they contain nonspecific hu type of human cell do exist and under some condi moral defense factors is admissible, but the lack of tions might excite an antibody response, while the convincing antineoplastic effects has removed second would suggest that antibodies could dam them from clinical or experimental interest, age cells through reaction with intracellular anti@@ It should be recognized that the production of gens. Strong evidence is also accumulating that a specific immune response, active or passives to diseases of the rheumatoid group, nephritis, tissue antigens does not automatically guarantee nephrosis, and periarteritis in man are of auto that the immune reaction so produced will act al1er@c etlQlogy (101, 119). detrimentally to the antigenic tissue. Specifically, In experimental therapeutic studies in cancer the assumption that antitumor antibodies will patients attempts have been made to utilize ac.@ necessarily inhibit tumor growth is. not justified tive and pa@ive immune mechanisms. Kelloch by the available experimental data. Specific im (87) in 199292autot.rausplanted irradiated, cancer mune tolerance (18, 19, 118) is a phenomenon in tissue in an atten@pt to sfimu1at@ immunity in can which an aetive immune reaction results intheun cer patients. Stone and co-workers (188) made opposed aeceptanee rather than the rejection of a similar studies using cancer tissue killed by freer. foreign antigen. Under certain circumstances,, the ing. Graham (65, 66) auth-inoculated killed cancer passive administration of antitu.mor serum will tissues prepared with Freun4@s adjuvants an4 re stimulate rather than inhibit tumor@growth. This ported a slight antineoplastic effect. The cytologic phenomenon has been studied by Casey, by Kaliss, criteria used for evaluation are, however, not gen@ and by Snell and. their co-workers (31,59, 84),.but erally accepted and in any case fail shortof a.thera@ the reason for these opposite responses is still Un peutic effect. Fiuney5 attempted autoimmuniza-. explained. The possibility that it represents a tion using cancer tissue in FreuzKL's adjuvant and cross-reaction of the antiserum with normal host reported the formation of serum antibodies detect tissues which is detrimental to their participation able by the tanned erythrocyte technic, and which in the rejection reaction deserves. consideration. after concentration caused regression of skin Martinez et al. (116) have reported that in mice metastases on direct inoculation. which were immune according to the criterion of Grace (692) demonstrated cytolysis of tumor accelerated transplant rejection, metastases from cells in lymphoma cutis after direct infiltration the primary tumor transplant continued to grow. with an antiserum prepared in rabbits. The pas Numerous other studies, however, testify that the sive immunity approach has also been attempted more frequent result of antibody administration is in the experimental treatment of human, cancer. inhibition of tumor growth, although such inhibi The most recent studies are by Murray (1926) and tion may be evident only if treatment. was started by Buinauskas et al. (929), who used antisera pre in the very early period after tumor transpiantar pared in horses and sheep respectively agaiast 1w- tion. man tumor tissues. M@irray reported subjective Experiments with virus-induced, tumors (like improvement and his clinical impression that life other virus infections) have shown only prophy was. prolonged, but no convincing datato support lactic rather than therapeutic effects from active a conclusion of specific anticancer effect. Buinaus or passive immunization, In,such studies a unique. kas et at. reported partial and transient shrinkage carcinogen which is presumably also an antigen of nodes in two of the three patients treated. The (i.e., the oucogeme virus) is known to be present. lack, of convincing therapeutic responses and the Unless this. agent is either nonantigenic oz@has theoretical objecti@is discussed al@ove certainly al4tigepic identity with the host tissues, or un1e4ss@

Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1960 American Association for Cancer Research. S0UTHAMâ€”Immunology and Cancer: Review 9285 through some phenomenon such as induced toler the importance of nonspecific immunity. This area ance the host fails to recognize this antigen as for is of considerable interest, however, since it is rela eign, it would reasonably be presumed that specific tively unexplored, because the multitudinous immune mechanisms would be capable of acting problems of specific immune reactions do not ap against the oncogenic virus. The fact that such ply and because of the clear evidence that proce mechanisms are not commonly effective in corn dures which repress nonspecific defense mecha bating the resultant tumor fits the hypothesis that . nisms also diminish host resistance to transplanted circulating antibody does not affect an intracellu cancer. lar pathogen or the cell in which it resides. Deficiencies of total complement activity (158, When a transplanted cell is foreign to the re 1792)or of complement components 1, 92,3, and 46 cipient, it follows that the host is likewise foreign have not been detected in cancer patients. to the grafted celL This scholastic nicety has Serum properdin level is correlated with tumor achieved scientific and potential clinical impor growth. This is illustrated by the progressive drop tance with the use of grafts of bone marrow or in serum properdin titers in mice bearing Sarcoma lymphoid tissues for the repair of complete reticu 180 (926)or Gardner lymphosarcoma (75, 76), and lo-epithelial system destruction after a high dose in rabbits with Brown-Pearce carcinoma (133). It of total-body irradiation for the eradication of is also apparent from the increased rejection rates leukemia. In this situation, a successful graft may of Sarcoma 180 in mice (927), of a benzpyrene-in react against its host with a resulting syndrome duced sarcoma in rats (1925), and of the human designated as â€œhomologousdiseaseâ€• (199). sarcoma H.S. #1 in conditioned rats3 when proper To summarize this discussion of the place of din is elevated following administration of small specific immune reactions in the management of doses of polysaccharide; and, conversely, by the human cancer: (a) The very possibility of anti impaired rejection of these same tumors and of neoplastic effects rests on the existence of antigens the human tumors H.Ep. #3 (135) and H.R. 1392 which are unique to neoplastic tissue, and against (74) in conditioned rats when properdin levels are which specific antibodies can be produced which depressed by massive doses of polysaccharide. In will inhibit cancer cell growth. (b) Recent studies man, too, properdin levels are generally low in with mouse leukemia and with established lines of patients with advanced cancer (44, 47, 157, 159, human cancer cells raise our hopes that such 178).1 Occasionally properdin inhibitors are de unique antigens might exist but as yet give no in monstrable in serum (46).' The rejection of homo dication of how widely a given cancer antigen may transplanted cancer cells is strikingly impaired in be distributed among various spontaneous tumors, those cancer patients with no detectable serum or whether cross-reactions with normal tissues properdin (178). It is evident, however, that the might be encountered. (c) If these antigenic re correlation between properdin and growth of spon quirements are fulfilled, prophylaxis by active im taneous or transplanted cancer is not necessarily a munization would theoretically be possible, but as causal relationship. It might be merely the result yet there are no experimental data to confirm or of a simultaneous but unrelated fluctuation in tu refute this possibility. (d) The possibility of thera mor growth and properdin level; or the properdin peutic usefulness further demands that methods titers might merely reflect abnormalities of some be devised to correct the immunologic inadequacy as yet unrecognized defense factors which are of the patient who has already failed to defend causally operative in the rejection of tumors. The himself against cancer. Of all experimental studies, fact that properdin has no cytocidal effect on hu only those of Corer and Amos and co-workers ap man cancer cells in tissue culture (179) is consist pear to fulfill the requirements of antitumor speci ent with this suggestion. The recent report by ficity and limited therapeutic effect. None of the Ross (156) that mice are protected against bac clinical experimentation with active or passive im terial infection by administration of properdin munization is adequate in quantity or in quality which had been denatured by boiling strongly sug to conclude that a specific anticancer effect has gests that the protective factor is not properdin been produced. however, neither this fact nor the itself, but other factors which vary in concert with naivetÃ©and even quackery which have character properdin levels. It must also be emphasized that, ized some of the uses of sera in cancer patients with the exception of the serum levels in cancer refute the theoretical possibility that therapeutic patients, all the observed relationships of proper effects might eventually be achieved through din to cancer concern transplanted tumors, and, specific immune mechanisms. â€˜D.G.Miller,J.M. Budinger,D. A. Karnofsky,Factors 92. By nonspecific immunologic mechanisms.â€” influencing host resistance to infection in chronic lymphatic Little is known of the factors, the mechanisms, or leukemia (in preparation).

even if it be found that properdin is active in the VL CONCLUSION rejection of transplanted tumors, it cannot be as In conclusion, lest the tone of this review seem sumed that the same mechanisms are operative too pessimistic concerning the possibility of cmi against spontaneous human cancer. cally useful application of inimunologic methods Elevation of properdin levels by the admiis in combating cancer, we should recall that there tration of small doses of polysaccharides has been already exists a fairly impressive array of antineo accomplished in experimental animals (98) and plastic chemicals which act directly on the cancer normal man (41, 164). In cancer patients, limitedâ€¢ cell. It is no exaggeration to say that some of these trials by Grimm7 and by Southam (171)' had no agents are as effective against certain neoplasms striking or sustained effect on properdin levels. as are most of the bacteriostatic agents which are This apparent failure to increase properdin levels so dramatically effective against infectious dis is not surprising in view of the great deficit of eases. The difference between infectious and nec I)roperdin observed by Southam and co-workers plastic diseases in responsiveness to chemotherapy in some cancer patients.1 Grimm has reported7 might well be due to the inadequacy of host de suggestive therapeutic effects from repeated small fenses in the latter. If this be true, even a slight doses of the bacterial polysaccharide â€œpyrexal,â€•improvement in host immune mechanisms might but even if such effects are confirmed it does not contribute significantly to the efficacy of chemo necessarily follow that they are an effect of proper therapy. This would seem to be a type of combina din. Polysaccharides have been used clinically for tion therapy which merits further study. the treatment of neoplastic disease in the form of Since Humpty Dumpty was evoked as an open Coley's mixed toxins and Shear's polysaccharides ing gambit, it seems appropriate to close by com for many years and unquestionably do produce paring the present situation of the cancer immu occasional clinical remissions. The possibility that nologist to hlumpty Dumptyâ€”with respect to the these materials work through stimulation of non wall which we are straddling between two great specific defense factors deserves consideration. disciplines of medical science, our extreme vulner The administration of properdin to correct the ability in assuming that position, the jabberwocky properdin deficit of patients with advanced nec quality of this and other discussions of this sub plastic disease is the most obvious and direct ap ject, and the unsatisfying note on which both proach to determine whether or not this material stories end. has any activity against cancer. Preliminary trials REFERENCES sufficient to demonstrate that human properdin is 1. AMA News, March 9, 1959, p. 9. Krebiozen, Cancer nontoxic and to demonstrate its rate of disappear and the AMA. ance have been carried out, but therapeutic trials @.AGOSIN, M.; CHRISTEN, R.; BADINAZ, 0.; GA&C, G.; have not yet been accomplished.' NEHGME, A.; Pzz@usno, 0.; and JARPA, A. Cortisone The possibility of administering nonspecific hu induced Metastases of Adenocarcinoma in Mice. Proc. Soc. Exper. Biol. & Med., 80: 1@8â€”31,195g. moral factors for the treatment of neoplastic dis 3. Aixis, H.; KURTZ, H. M.; Ka&au@n, P. I.; WEIMER, ease has no apparent theoretical objections but H. E.; RYAN, H. M.; and JAMESON, E. In Vivo and in does propose numerous practical problems. The Vitro Studies of the Action of Guinea Pig Serum against production of such agents from human blood re the Ascites Form of the Murphy-Sturm Lymphosarcoma. Cancer Research, 18:1309â€”13, 1958. quires tremendous uantities of blood but could 4. Aasos, D. B. and DAY, E. D. Passive Immunity against probably be accomplished without loss of the Four Mouse Leukoses by Means of Isoimmune Sera. presently used serum fractions. A human tissue Ann. N.Y. Acad. Sc., 64:851â€”58, 1957. source such as placentas might also be used. Such 5. Aaios, D. B.; Goaua, P. A.; and Mzxur.8KA, Z. B. substances might also be obtained from animal An Analysis of an Antigenic System in the Mouse (the H-@ system). Proc. Roy. Soc., s. B, 144:869-80, 1955. sources, but this possibility carries with it the 6. APTEKMAN, P. M.; Luwis, M. R.; and KING, H. D. probability of more rapid destruction of the heter A Method of Producing in Inbred Albino Rats a High ologous protein and the danger of foreign protein Percentage of Immunity from Tumors Native in Their Strain. J. Immunol., 52:77â€”86, 1946. reactions. The known or postulated actions of 7. ARCOMANO,J. P.; BAaxIrrr, J. C.; and BOTrONE, J. J. other nonspecific cellular and humoral factors have Spontaneous Disappearance of Pulmonary Metastases been mentioned above. As yet the study of such following Nephrectomy for Hypernephroma. Am. J. factors has rarely been extended to man, and they Surg., 96:703â€”4, 1958. 8. AXELROD, A. E.; and PRUZANSKY, J. The Role of the are still so poorly understood that not even specu Vitamins in Antibody Production. Ann. N.Y. Acad. Sc., lation seems possible. 63:@0@â€”14,1955. 9. BARLOW, J. L.; VAN VUNAKIS, H.; and LEVINE, L. R. Grimm, personal communication, June @0,1958. Studies of the Inactivation of Phage by the Properdin

System. I. Evidence for Complement, Properdin and 82. Cou.um, R. C. Further Experimental Studies on Sympa MagnesiumRequirements.3. Immunoh,80:389-48, 1958. thetic Ophthalmia. J. Ophtbalmol., 36: 150-61, 1958. 10. BARRm-r, M. K. The Influence of Genetic Constitution 83. Cowvna, J., and GL@r@ei,LE. Experimental Iso-immune upon the Induction of Resistance to Transplantable Adrenalitis. Immunology, 1: 172â€”78,1958. Mouse Tumors. J. Nat. Cancer Inst., 1:387-93, 1940. 84. Cox, H. R. The Spotted-fever Group, p. 621. In: T. M. 11. â€”â€”. A Critical Analysis of â€œTumor Immunity.â€• J. Rrvnns (ed.), Viral and Rickettsial Infections of Man. Chron. Dis., 8:136â€”57, 1958. Philadelphia: Lippincott, 1952. 12. BEARD, J. W.; Sii@ap, D. G.; and Ecxnur, E. A. Tumor 35. DAoo, C. P.; KARNOFRKY,D. A.; and RODDY,J. Growth Viruses. Adv. Virus Research, 3: 149â€”97,1955. of Transplantable Human Tumors in the Chick Embryo 13. Bzcrn, E.L. ConcerningtheMechanism of Complement and Hatched Chick. Cancer Research, 16:589â€”94,1956. Action. IV. The Properties of Activated First Component 86. DAY, E. D., and PRESSMAN, D. Purification of Tumor of Guinea Pig Serum. J. Immunol., 82:43â€”51, 1959. localizing Antibodies. Ann. N.Y. Aced. Sc., 69:651â€”57, 14. BERAR, A. J., and TAL, C. Experimental Liver Necrosis 1957. Produced by the Injection of Homologous Whole Liver 37. DONALDSON,D. M., and MITCHELL, J. R. Immunization with Adjuvant. J. Path. & Bact., 77:591â€”96, 1959. against Ehrlich's Ascites Carcinoma with X-irradiated 15. Binsun, S. M.; ERLANGER, B. F.; AGATE, F. J.; and Tumor Cells. Proc. Soc. Exper. Biol. & Med., 101:204-7, LIEBERMAN, S. Antigenicity of Steroid-Protein Conju 1959. gates. Science, 129:564â€”65, 1959. 38. DULANEY. A. D., and ARNESEN, K. Cytotoxic Action of 16. BERG, J. Inflammation and Prognosis in Breast Cancer. Antisera to Cell Components of Normal and Leukemic A Search for Host Resistance. Cancer, 12:714â€”@0,1959. Mouse Spleens. Proc. Soc. Exper. Biol. & Med., 72: 17. BICKNELL, F., and Parsco!rr, F. The Vitamins in Medi 665â€”68,1942. cine. New York: Grune & Stratton, 3d ed., p. 784. 1953. 39. DURAN-REYNALa,F. Tissue Permeability and the Spread 18. BILLINGISAM, R. E.; BRENT, L.; and MEDAWAR, P. B. ing Factors in Infection. A Contribution to the Host: Quantitative Studies on Tissue Transplantation Immuni Parasite Problem. Bact. Rev., 6: 197â€”252,1942. ty. III. Actively Acquired Tolerance. Phil. Trans. Roy. 40. ECKER, E. E. Complement. Ann. Rev. Microbiol., 2: Sc., s. B, 239:857â€”414, 1956. 255â€”68,1948. 19. . Acquired Tolerance of Skin Homografts. Ann. 41. EICHENBERGER,E., and IsunER, H. Das Verhalten des N.Y. Acad. Sc., 59:409â€”iS,1955. Properdins nach intravenoser Injektion bakterieller Lipo 20. BITTNER, J. J. Recent Studies on Mouse Mammary Tu lysaccharide beim Menschen. Helv. Physiol. Acta, 14: mor Agent. Ann. N.Y. Acad. Sc., 68: 636â€”48, 1957. 64â€”66,1956. 21. . Studies on Mammary Cancer in Mice and Their 42. ENGELL, H. C. Cancer Cells in the Blood. Ann. Surg., Implications for the Human Problem. Tex. Rep. Biol. 149:457â€”62,1959. & Med., 15:@11â€”26,1957. 43. EVERSON,T. C., and COLE, W. H. Spontaneous Regres 2@. BJORKLUND,B.Antigenicity of Malignant and Normal sion of Cancer: Preliminary Report. Ann. Surg., 144: Human Tissues by Gel Diffusion Technique. Internat. 366â€”80,1956. Arch. Allergy & Appi. Immunol., 8: 179â€”92,1956. 44. EYQUEM, A. Importance de la properdine en clinique. 23. BJORKLUND, B.; LUNDBLAD, G.; and BJORKLUND, V. Trans. 6th Cong. European Soc. of Haemat., pp. 968-68, Antigenicity of Pooled Human Malignant and Normal 1957. Tissues by Cyto-immunological Technique: II. Nature 45. EYQUEM, A.; FRANCQ, J. C.; and DELMONTE, L. La of Tumor Antigen. Internat. Arch. Allergy & Applied Properdine. La Biol. Med., 48:21â€”51, 1959. Immunol., 12:241â€”61, 1958. 24. B000MOLETS, A. A. Antireticular Cytotoxic Serum as 46. EYQtTEM,A.; Fiu.r@cq, J. C.; GUYOT-,JEANNIN,N.; and a Means of Pathogenic Therapy. Am. Rev. Soviet Med. JACQUELINE, F. La Properdine au cours des rhumatismes infiammatoires chroniques. Ann. de L'Institut Pasteur, 1:101â€”12,1943. 95:748â€”58, 1958. 25. BOYDEN, S. V. The Adsorption of Proteins on Erythro cytes Treated with Tannic Acid and Subsequent Hemag 47. EYQUEM, A., and Timus, J. L. Observations on Serologi glutination by Antiprotein Sera. J. Exper. Med., 93: cal Determination of Properdin. Vox Sang, 2: 61-62, 107â€”20,1951. 1957. 26. BRADNER, W. T., and CI@.&iurE,D. A. Serum Properdin 48. FELDMAN,H. A. The Relationship of Toxoplasma Anti Levels in Mice with Sarcoma 180. Proc. Am. Assoc. body Activator to the Serum-Properdin System. Ann. Cancer Research, 2:282, 1958. N.Y. Aced. Sc., 66:263-67, 1956. 27. BRADNER, W. T.; Cz@tnxx, D. A.; and Srocx, C. C. 49. Fnr@, M. A.; Sssrra, P.; and Ro'nn4tu@, M. V. Antibody Stimulation of Host Defense against Experimental Can Production in BALB/c Mice Following Injection of Ly cer. I. Zymosan and S-iSO in Mice. Cancer Research, ophilized Tumor S621 in Freund's Adjuvant. Proc. Soc. 18:847â€”51, 1958. Exper. Biol. & Med., 90:590â€”98, 1955. 28. BRUMFIELD,H. P. A Factor of Complement Inactivated 50. FOLEY, E. J. Attempts To Induce Immunity against by Histamine or Ethylenediamine. J. Immunol., 72: Mammary Adenocarcinoma in Inbred Mice. Cancer Re 898â€”97,1958. search, 13:578â€”80, 1953. 29. BumAussas, P.; MCCREDIE, J. A.; BROWN, E. R.; and 51. . Antigenic Properties of Methylcholanthrene Cor@u,W. H. Experimental Treatment of Tumors with induced Tumors in Mice of the Strain of Origin. Cancer Antibodies. A.M.A. Arch. Surg. (in press). Research, 13:885â€”87, 1953. 80. Bunnows, D. Schultz-Dale Test for Detection of Specific 52. Fox, F.; DAVIDSON, J.; and THoMAS, L. B. Maturation Antigen in Sera of Patients with Carcinoma. Brit. M. of Sympathicoblastoma into Ganglioneuroma. Report J., 1:868â€”70, 1958. of 2 Patients with 20- and 46-Year Survivals, Respective 31. CASEY, A. E.; LASTER,W. R.; and Ross, G. L. Sustained ly. Cancer, 12:108-16, 1959. Enhanced Growth of Carcinoma E0771 in C57 Black 53. FRANCQ,J. C.; EYQUEM,A.; and GUYOT-JEANNIN,N. Mice. Proc. Soc. Exper. Biol. & Med., 77:858â€”62, 1951. Le pouvoir inhibiteur du serum vis-Ã -vis du bacteriophage

T@2r+ et in properdin.Ann. de L'Institut Pasteur, (Gardner Lymphosarcoma 6C3HED). Am. J. Path., 34: 96:178â€”83, 1959. 911â€”20,1958. 54. FREUND, J.; LIPTON, M. M.; and THOMPSON,G. E. 76. Hnunu'r, P. A.; KRAEMER, W. H.; and Pu@msun, L. Aspermatogenesis inthe Guinea Pig Induced byTesticular The Effects of Components of Guinea Pig Serum on Tissue and Adjuvants. J. Exper. Med., 97:711â€”26, 1958. Lymphosarcoma 6C3HED in CSH Mice. Blood, 13: 55. GESSLER,A. E.; Bmmzn, C. E.; and PARKINSON,M. C. 732â€”89,1958. I. A New and Rapid Method for Isolating Virusesby 77. HEYMANN, W.; HACKEL, D. B.; HARWOOD, S.; WusoN, Selective Fluorocarbon Deproteinization. Trans. N.Y. S. C. F.; HUNTER, J. L. P. Production of Nephrotic Aced.Sc., 18:701â€”8,1956. Syndrome in Rats by Freund's Adjuvants and Rat Kid 56. GINSBERG, H. S., and WEDOWOOD,R. J. Properdin and ney Suspensions.Proc. Soc. Exper. Biol. & Med., 100: the Inactivation of Viruses. Ann. N.Y. Aced. Sc. (in 660â€”64,1959. piess). 78. Hmti@zcrro, R.; GOLDSTEIN, M.; and PRESSMAN, D. Reac 57. GOLDFEDER, A. Induced Resistance in Inbred Homozy tions of Antisera Prepared against HeLa Cells and Normal gous Rats to a Lymphosarcoma Autogenous to the Strain. Fetal Liver Cells with Adult Human Tissues. Cancer Proc. Soc. Exper. Biol. & Med., 59: 104â€”9,1945. Research, 18:668â€”69, 1958. 58. GOLDSTEIN, G., and Mmvuc, Q. The Reversible and 79. HinScE, H. M.; BITTNER, J. J.; Coin, H.; and IvEissEN, Irreversible Toxic Effects of anti-HeLa Cell Rabbit Serum J. Can the Inbred Mouse be Immunizedagainst Its upon Human Cell Lines in Tissue Culture. J. Immunol. Own Tumor? Cancer Research, 18:844â€”46, 1958. 80:100â€”105, 1958. 80. HmsT, A. E., and BERGMAN, R. T. Carcinoma of the 59. GORER, P. A. Some Recent Work on Tumor Immunity. Prostate in Men 80 or More Years Old. Cancer, 7: Adv. Cancer Research, IV : 149â€”86,1956. 186â€”41,1954. 60. GOnER, P. A., and Assos, D. B. Passive Immunity in 81. Huiuii, H. Infektionsresistenz bei MÃ¤usen nach Vorbe Mice against CS7BL Leukosis EM by Means of Iso handlung mit Lipopolysacchariden. Proc. 6th Cong. Euro immune Serum. Cancer Research, 16:838â€”43, 1956. pean Soc. Haemat., 2:S938â€”88, 1957. 61. Gnacz, J. T., and DAO, T. L. Etiology of Inflammatory 82. Isuxxa, H. C. The Properdin System. Vox Sang, 1: Reactions in Breast Carcinoma. Surg. Forum, 9: 611â€”14, 8-26, 1956. 1958. 83. KABAT,E.A.; Wors, A.; and Bzzza, A. E. The Rapid 62. GRAcE, J. T.; Goiw@, F.; TAYLOR,W. L.; and CARLSON, Production of Acute Disseminated Encephalomyelitis in R. I. The Effect of LocalInfiltrationof a Heterologous Rhesus Monkeys by Injection of Heterologous and Ho Anti-serum of Lymphoma Cutis in Man. Surg. Forum, mologous Brain Tissue with Adjuvants. J. Exper. Med., 8:185â€”87, 1957. 85:117â€”30,1947. 63. GRAcE, J. T., and Koimo, T. Investigations of Host 84. Kuiss, N. Induced Alteration of the Normal Host-Graft Resistance in Cancer Patients. Ann. Surg., 148:638-41, Relationships in Homotransplantation of Mouse Tumors. 1958. Ann. N.Y. Aced. Sc., 59:385â€”91, 1955. 64. GRAF, L., and RAPPORT, M. M. C-Reactive Protein in 85. KARUSH, F. Ford Hospital Symposium on Mechanisms Cancer: A Study of 216 Patients. Cancer, 11:255-58, 1958. of Hypersensitivity. Quantitative Measurements of Het 65. GRAHAM, J. B., and GRAHAM, R. M. Antibodies Elicited erogeneity among Antibodies. pp. 19â€”26.Boston: Little, by Cancer in Patients. Cancer, 8: 409â€”16,1955. Brown & Co., 1959. 66. . The Effect of Vaccine on Cancer Patients. Surg. 86. K&i@zoN, D. T., and BUSSELL, R. H. Studies of the Gyn. & Obst., 109: 131â€”38,1959. Nonspecific Inactivation of Newcastle Disease Virus by 67. GREENE, H. N. S. The Significance of the Heterologous Mammalian Scra. Ann. N.Y. Aced. Sc., 83:539-50, 1960. Transplantability of Human Cancer. Cancer, 5:24â€”44, 87. Kzawc.u, T. H.; CHAMBERS, H.; and Russ, S. An 1952. Attempt To Produce Immunity to Malignant Disease 68. GROSS, L. Intradermal Immunization of CSH Mice in Man. Lancet, 1:217â€”19, 1922. against a Sarcoma that Originated in an Animal of the 88. KESSEL, L. Spontaneous Disappearance of Bilateral Pal Same Line. Cancer Research, 3:326â€”33, 1948. monary Metastases. J.A.M.A., 169:1737â€”39, 1959. 69. . Pathogenic Properties, and â€œVerticalâ€•Trans 89. KESSLER, S., and MARTIN, G. The Abderhalden Reaction. mission of the Mouse Leukemia Agent. Proc. Soc. Exper. A Reviewof the Literatureon the Defense Proteinases Biol. & Med., 78:342â€”48,1951. (Abwehrfermente). Exper. Med. & Surg., 16:190-212, 70. HARRIS, R. J. C. Some Aspects of Virus-induced Tumors. 1958. J. Chron.Dis., 8:58â€”87,1958. 90. KIDD, J. G. Regression of Transplanted Lymphomas 71. HAuscnx@t, T. S. Immunologic Aspects of Cancer. Cancer Induced in Vivo by Means of Normal Guinea Pig Serum Research, 12:615â€”33, 1952. (I &II). J. Exper.Med.,98:565-606, 1953. 72. HEIDLEBERGER, M.; MACLEOD, C. M.; KAISER, S. J., 91. KLARNER, P. Regressionen des Yoshida-Sarkoms nach and ROBINSON, B. Antibody Formation in Volunteers einmaliger Injektion eines Lipopolysaccharidien aus E. Following Injection of Pneumococci or Their Type coli. Ztschr. Krebsforsch., 62:291â€”96,1958. Specific Polysaccharides. J. Exper. Med., 83:808-20, 92. KORNGOLD,L., and LIPARI, R. Tissue Antigens of Human 1946. Tumors Grown in Rats, Hamsters, and Eggs. Cancer 73. HERBERT, P. H., and DE Vanos, J. A. Administration Research, 15:159â€”61, 1955. of ACTH to Normal Human Subjects. Effect on Leuko 93. KOROerELEVA, V. S.SimilaritiesandDifferencesofSpe cytes in the Blood and on Circulating Antibody Levels. cific Antigens of Cancer in Man. Bull. Exper. Biol. Endocrinology, 44:259â€”73, 1949. & Med., 44:987â€”93,1957. 74. Hmuiu'r, P. A., and Kiu.mina, W. H. The Possible Role 94. K0SAN.I, T. A New Phospholipid, Malignolipin in Human of the Properdin System in Transplantable Cancer. The Malignant Tumors. Science,127:1176â€”77,1958. EffectofZymosan on TransplantableHuman Carcinoma. 95. Kiuvrr,W., and Goon, R. A. SimultaneousOccurrence Cancer Research, 16:1048â€”52, 1956. of Mongolism and Leukemia. A.M.A. J. Dis. Child., 75. . The Properdin System in Transplantable Cancer 94:289â€”93, 1957.

96. LANDSTEINER, K. The Specificity of Serological Reac Mammary Tumor AssOciated with the Development ot tions. Cambridge: Harvard University Press, 1945. Immunity in Mice. Cancer Research, 17:205â€”7,1957. 97. LANDSTEINER, K., and Ca4sE, M. W. Experiment on 117. MCALLISTER,R. M.; GRtnwsns, P. W.; CORIELL,L. L.; Transfer of Cutaneous Sensitivity to Simple Compounds. MARSHAK, R. R. The Effects of Heterologous Immune Proc. Soc. Exper. Biol. & Med., 49:688-90, 1942. Serums upon Hela Cells in Vitro and Rat Hela Tumors 98. LANnY, M., and PILLEMER, L. Elevation of Properdin in Vito. J. Nat. Cancer Inst., 21:541â€”55,1958. Levels in Mice Following Administration of Bacterial 118. MEDAWAR, P. B. The Harvey Lectures, 1956â€”1957,pp. Lipopolysaccharides. J. Exper. Med., 100:823â€”83,1956. 144-76. The Immunology of Transplantation. New York: 99. . Increased Resistance to Infection and Accom Academic Press, 1958. panying Alteration in Properdin Levels Following Ad 119. Mzi@ona, R. C., and ORTEGA, L. G. Analytical Pa ministration of Bacterial Lipopolysaccharides.J. Exper. thology. ifi. New Observations on the Pathogenesis Med., 104:883â€”409,1956. of Glomerulonephritis, Lipid Nephrosis, Periarteritis No 100. LANDY,M., and Sanaa, Mi 3. Similarity of Host Re doss, and SecondaryAinyioidosis in Man. Am. J. Path., spouses Elicited by Polysaceharides of Animal and Plant 32:455-90, 1956. Origin and by Bacterial Endotoxins. J. Exper. Med., 120. Munxm, V. Chemical Mediators in Relation to Cytologic 1@6:77â€”97,1957. Constituents in Itiflammation. Am. J. Path., 34:921-41, 101. LANGE, K.; SLOBODY,L.; and S'rwia, B. Treatment of lOSS. Nephrotic Syndrome with Interrupted ACTU or Oral 121. MuncH, E., and Nicsioz., C. A. The Effect of Pyridoxine Cortisone Therapy. Proc. Soc. Exper. Biol. & Med., Deficiency on Mouse Sarcoma. Cancer Research, 19: 82:815â€”17,1958. 279-85@ 1969. 102. LAw, L. W. Maternal Influence inExperimental Leuke 122. Mnisa, D. G., and Hau, T. C. The Action of Cytotoxie mia of Mice. Ann. N.Y. Aced. Sc., 57@575-85, 1954. Antisera on the Hela Strain of Human Carcinoma. Cancer [email protected]@wauncB, H. S. The Dalayed@ Type of Allergic Infiam Research, 16:806-12, 1956. matory Response, Am. J. Med., 2G:428-47, 1956. 123. MITOHISON, N. A Studies on the Immunological Re 104. . Similarities between Homograft Rejection and spouse to Foreign Tumor Transplants in the Mouse. Tuberculin-IypeAllergy: a Review ofRecent Experimen I. The Role ofLymph Node CellsinConferringImuiunity tal Findings. Ann. N.Y. Aced. Sc., 64:826-38, 1957. by Adoptive Transfer@J. Exper. Med., 102:157â€”77,1955. 105. LEPOW,I.Ii. FordHospital Symposium on Mechanisms 124. . Isoantibody against a Tumor. Transplantation of Hypersensitivity. Complement: A Review (Including Bull., 2:98â€”94,1955. Esterase Activity), pp. 267â€”79.Boston: Little, Brown 125. MODIcA,F.,and Fuzsunots@,0. Sal rapportitra zymosan,. & Co., 1959. properdina e tumori. Tumori@44:549-54, 1968. 106. Lspow, L H.; RATN0FF, th D.; and Lzvi-, L. Studies on 126. Mumur, G. Experimentainlmmunity in Cancer. Canad. the Activation of a Proesterase Asaoeiated with Partially M. Assoc. J., 79:249â€”59,1958. Purified First Component of Human Complement. J. Ex 127. MYERBVRG, R. J. Levels of Properdin in Patients with per. Med., 107:451â€”74,1958 Carcinoma. Am. J. Clin. Path., 31:415-18, 19@). 107. Lmvis, M. R. Immunity in Relation to 1:2:5:6 Dibenz 128. NELeON, R. A. A Hypothetical Role of Erythrocytes anthracene-induced Sarcomata. Bull. Johns Hopkins in Defense against Bacteria and Viruses. Proc. RoyaP Hospital, 67:825â€”44, 1940. Soc. Med., 49:55-58, 1956. 108. LEwis, Mi R., and APTEKMAN,P. M. Atrophy of Tumor 129. . An Alternative Mechanism for the Properdin Caused by Strangulation and Accompanied by Develop System. J. Exper. Med., 108:515-35, 1958. ment of Tumor Immunity in Rats. Cancer, 5:411â€”18, 130. Novus, W. F., and Mm.wns, R. C. Fluorescent Antibody 1952. Detection of the Antigens ol the Shope Papilloma Virus 109. Luw, H. E., and ASHLEY, 0. Specificity of the Universal in Papillomas of the Wild and Domestic Rabbit. J. Serological Reaction in the Diagnosis of and Staging of Cancer. Cancer,5:406â€”10,1952. Exper. Med., 106:555â€”62,1957. 110. Luasmun, T. On the Nature of Immunity to Implanted 181. Ouvna, C. P. Factors Affecting Susceptibility in Cancer Malignant Tumors. Lancet, 212: 116-22, 1927. Occurrence. Texas Rep. Biol. & Med., 10:205â€”16,195@. 111. MacDowm@, E. C.; PorrEa, J. S.; and TAYLOR,M.J. 182. . Studies on Human Cancer Families. Ann. N.Y. Immunization of Mice Naturally Susceptible to a Trans Acad. Sc., 71:1198â€”1212,1958. planted Leukemia. Proc. Soc. Exper. Biol, & Med., 32: 188. Owsc, C.; Hor.ounax, V.; and B&wrv, M. The 84â€”86,1934. Properdin System in a Tumorous Disease. ifi. The 112. MAKARI,J. G. Detection of Antigens in Sera of Patients Time Sequence of Changes in the Level of Properdin with Neoplastic Disease by Schultz-Dale Test. Brit. in Rabbits with. Brown-Pearce Carcinoma. Neoplasma, M. J., 2:858â€”61,1958. 4:8â€”6,1957. 118. MALMGREN,R.A.; BENNISoN,B. E.; ArmsmsoN,B. F.; 134. Ovma@tw,J. R., and H.&@iAN,R.Effect of Cortisonc on and Riszsrr, C. C. A Serologic Study of the Microsome Mumps Antibody Formation in Rabbits. Proc. Soc. Fraction of Normal and Neoplastie Mouse Tissues. J. Exper. BioL & Med., 82:427â€”80,1953. Nat. Cancer Inst., 11:1277â€”86, 1951. 135. Ptui, J. E. The Use of Zymosan in Explorations for 114. MA@qxowsxx, Z. T.; YAMASH1TA,Mi; and Dmzxu, I. C. OptimumConditioningofRataforHumanTumors Trans.@ Effect of Candida GwiiliermondiPolysaccharide on Trans plantation man Experimental Chemotherapy Program. plantable Mouse Sarcoma 87. Proc. Soc. Exper. Biol. Proc. Am. Assoc. Cancer Research, 2:138-89, 1956. & Med., 96:79-80, 1957. 186. PENROSE,L.S. Mongolian Idiocy (Mongolism) and Ma 115. M@tii@i,LS., and WF@zw, W. H. A Specific Precipitin ternal Age. Ann. N.Y. Acad. Sc., 57:404â€”SOS,1954. Antiserum for Carcinoma Protein. Am. J. Cancer, 39: 137. P@u@trs,J.H.; BnauN, W.;and PLEscu@,0.J. Immuno 860-64, 1940. chemical Study of a Bacterial DNA. J. Am. Chem. 116. MARTINEz,C.;Ausr, J. B.; Bn'rNsm,J. J.; and Goon, Sec., 80:2710â€”14,1958. R. A. A Continuous Growth of Isotransplants of a 138. Pzu,zatna, L. The Nature of the Properdin System and

Its Interactions with Polysaccharide Complexes. Ann. 158. Rorrnio, A., and LEvy, A. L. Behavior of Total Serum N.Y. Aced. Sc., 66:288-48, 1956. Complement in Hodgkin's Disease and Other Malignant 189. PILLEMER,L.;BLuss, L.; LEPOW,I. H.; Roes, 0. A.; Lymphomas. Blood, 14:246â€”54, 1959. TODD, E.; and WARDLAW, A. C. The Properdin System 159. RorrlNo, A.; LEvY, A. L.; and CONTE,A. A Study of the and Immunity: I. Demonstration and Isolation of a Serum Properdin Levels of Patients with Malignant Tu New Serum Protein, Properdin and Its Role in Immune mors. Cancer, 11:351â€”56, 1958. Phenomena. Science,120:279â€”85,1954. 160. ROWLEY,D. Stimulation of Natural Immunity to Eache 140. PuLEMER, L.; Ltrmy, M.; and SHEAR, M. J. The Pro richia coli Infections. Observations on Mice. Laneet, perdin System and Immunity. VII. Alterations in Proper 1:252â€”34,1955. din Levels and Resistance to Infection in Mice Following 161. SACIIS,L., and FELDMAN,M. Cytotoxic Antibodies in the the Administration of Tissue Polysaccharides. J. Exper. Homograft Reaction. J. Nat. Cancer Inst., 21:563â€”78, Med., 106:99â€”110,1957. 1958. 141. PlUEMER, L., and Ross, C. A. Alterations in Serum 162. SALK, J. E., and WAim, E. N. Some Characteristics of Properdin Levels Following Injection of Zymosan. Sci a Continuously Propagating Cell Derived from Monkey ence, 121:732â€”38, 1955. Heart Tissue. Science, 126: 1838â€”39,1957. 142. PILLEMER,L.; SCHOENBERG,M. D.; BLUM, L.; and Wtmz, 163. SANDBERG.A.A.; MooRE,G. E.; and CROSSWRITE,L.H. L. Properdin System and Immunity. II. Interaction The Frequency of Tumor Cells in the Bone Marrow and of the Properdin System with Polysaccharides. Science, Blood. Cancer, 11:1180â€”86, 1958. 122:545â€”49, 1955. 164. SANFORD, J. P., and LANDY, M. Endotoxic Effects Pro 148. PIYARATN,P.Relative Incidence of Malignant Neoplasms duced in Man by a Purified Bacterial Polysaccharide. in Thailand. Cancer, 12:693â€”96, 1959. Clin. Res. Proc., 4: 134â€”35,1956. 144. Foot., E. H., and DUNLAP, G. R. Cancer Cells in Blood 165. SEAL, S. H. Silicone Flotation: A Simple Quantitative Stream. Am. J. Cancer, 21:99-102, 1984. Method for the Isolation of Free-floating Cancer Cells 145. PRESSMAN,D. Radiolabeled Antibodies. N.Y. Acad. Sc., from the Blood. Cancer, 12:590â€”95, 1959. 69:644â€”50, 1957. 166. SEEGAL,B. C. Ford Hospitsl Symposium on Mechanisms 146. PRINCE, J. E. ; FARDEN, J. C. ; NtrrINr, L. G. ; SPERTI, of Hypersensitivity. In Vivo Localization of Specific G. S. Induced Resistance to an Indigenous Transplant Antiorgan Sera: Relation to Occurrence of Renal Lesions, able Mouse Tumor. Cancer Research, 17:812â€”16, 1957. pp. 143â€”54.Boston: Little, Brown & Co., 1959. 147. RAGAN, C. ; LArrna, R.; BLurrr, J. W. ; VAILLANCOURT, 167. SKAPIER, J. Therapeutic Use of Antireticular Cytotoxic DR G.; JESSAR, R. A.; and EPSTEIN, W. The Effect of Serum (ACS) in Hodgkin's Disease. Cancer Research, ACTH and Cortisone upon Infection and Resistance. 7:369â€”71, 1947. In: G. SCHWARTZMAN(ed), pp. 46â€”55.New York: Co 168. SairrE, R. R.; TEoa&s, L. B.; HILBERO, A. W. Cancer lumbia U. Press, 1953. Cell Contamination of Operative Wounds. Cancer, 11: 148. RAPP, H. J. Mechanism of Immune Hemolysis: Recogni 53â€”62,1958. tion of Two Steps in the Conversion of EAC' 1,4,2 to E5. 169. SNELL, G. D. Incompatibility Reactions to Tumor Homo Science, 127:234â€”36, 1958. transplants with Particular Reference to the Role of the 149. RAPPORT, M. M.; GRAF, L.; Snirsiu, V. P.; and ALONZO, Tumor. Cancer Research, 17:2â€”10,1957. N. F. Immunochemicel Studies of Organ and Tumor 170. SNYDERMAN, R. K. Clinical Application of Embryonic Lipids. VT. Isolation and Properties of Cytolipin H. Skin Grafts. Ann. N.Y. Aced. Sc., 73:561-63, 1958. Cancer, 12:438â€”45, 1959. 171. Sotrra@a@, C. M. Studies of Properdin in Cancer Patients. 150. REBUCK, J. W., and MELLINGER, R. C. Interruption J. Clin. Invest., 37:983, 1958. by Topicel Cortisone of Leukocytic Cycles in Acute 172. Sou'rasas, C. M., and GOLDSMITH,Y. Effect of Nitrogen Inflammation in Man. Ann. N.Y. Aced. Sc., 56: 715â€”32, Mustard on Serum Complement in Vitro and in Patients 1953. with Neoplastic Disease. Proc. Soc. Exper. Biol. & Med., 151. REICH, C. Apparent Recovery in Chronic Lymphocytic 76:430â€”32, 1951. Leukemia. Report of a Case with Five-Year Remission 173. Soirrnazs, C. M.; GoLDSssrra, Y. ; and BURcHENAL, J. H. and No Clinical or HematologicalEvidence of the Disease. Heterophile Antibodies and Antigens in Neoplastic Dis J.A.M.A.,170:169â€”72,1959. eases. Cancer, 4: 1036â€”42,1951. 152. RIcE, C. E. The Interchangeability of Complement Com 174. Soum&st, C. M., and GREENE, E. I.. Lack of Effect ponents of Different Animal Species. I. Literature Survey. of Properdin System on West Nile and Mengo Viruses. Canad. J. Comp. Med., 14:869â€”79,1950. Ann. N.Y. Aced. Sc., 83:533â€”88, 1960. 153. RIGLER, L. G. A Roentgen Study of the Evolution of 175. SOUTEAM,C. M., and MooRE, A. E. Induced Immunity to Carcinoma of the Lung. J. Thoracic Surg., 34:288â€”97, Cancer Cell Homografts in Man. Ann. N.Y. Aced. Sc., 1957. 73:635â€”51,1958. 154. ROBERTS,J. C., and DIXON, F. J. The Transfer of Lymph Node Cells in the Study of the Immune Response to 176. Sotrniaar, C. M.; MooRE, A. E.; and Rao@ns, C. P. Foreign Proteins. J. Exper. Med., 102:379â€”92, 1955. Homotransplantation of Human Cell Lines. Science, 125: 155. Rorr'r, I. M., and Do@cu, D. Ford Hospital Sym 158â€”60,1957. posium, pp. 325-47. Mechanisms of Hypersensitivity, 177. Sourasas, C. M.; NOYES, W. F.; and MELLoiss, R. The Incidence, Nature, and Significance of Autoanti Virus in Human Cancer Cells in Vivo. Virology, 5: bodies in Thyroid Diseases. Boston: Little, Brown & 395â€”98,1958. Co.,1958. 178. SOUTEAM, C. M., and PIILENRR, L. Serum Properdin 156. Ross, 0. A. Experimental Studies of the in vivoRelation Levels and Cancer Cell Homografts in Man. Proc. Soc. ship of the Properdin System to Resistance to Infection. Exper. Biol. & Med., 96:596-001, 1957. Am. J. Path., 34:471â€”85,1958. 179. Souraas, C. M.; TAI, M.; and GREENE, E. L. Studies of 157. Rornrio, A.,and LEvY, A. L. Serusn-ProperdinLevels the Properdin System in Human Cancer Cell Cultures. inPatientswithHodgkin'sDiseaseand Carcinoma.Can Proc. Soc. Exper. Biol. & Med., 102:68-67, 1959. cer, 10:877â€”83, 1957. 180. Sou'rRAM, C. M.; THOMSON,A. E.; BURCHENAL,J. H.

False PositiveTrichina PrecipitinReactionsin Neoplastic 200. VmunAEN, A. Opera ex Domo Biologiae Hereditariae Disease. Proc. Soc. Exper. Biol. & Med., 72:354-57, 1949. Humanae Universitatis Hafnensis, Vol. 13 (contributions 181. SPAIN, D. M.; Mowanrr, N.; and HABER, A. Studies from the Univ. Institute for Human Genetics, Copen of the Cortisone Effects on the Inflammatory Response. hagen). English translation published by H. K. Lewis I. Alterations of the Histopathology of Chemically In & Co., London. Heredity in Human Leukemia and Its duced Inflammation. J. Lab. & Clin. Med., 39:383â€”89, Relation to Cancer, p. 279, 1947. 1952. 201. WAKSMAN,B. H., and AdAMS, R. D. Allergic Neuritis. 182. SPENCER, R. R. Tumor Immunity. J. Nat. Cancer Inst., An Experimental Disease of Rabbits Induced by the 2:317â€”32,1942. by the Injection of Peripheral Nervous Tissue and Ad 185. Spstn@,H. J. Cancer Cells in Pleural Cavity Washings. juvants. J. Exper. Med., 102:213â€”35, 1955. Cancer, 11: 1222â€”25,1958. 202. WARDLAW, A. C., and PILLEMER, L. The Properdin 184. STEmEa, P. E.; MAIMON,S. N.; PAusEN, W. L.; and System and Immunity. V. The Bactericidal Activity of KIRSNER, J. B. Gastric Cancer, Morphologic Factors the Properdin System. J. Exper. Med., 103:553-75, 1956. in Five-Year Survival after Gastrectomy. Am. J. Path., 203. WATME, A. L. ; MOORE, G. E. ; and HATIBOOLU, I. Cancer 24:947â€”09, 1948. Cells in Thoracic Duct Lymph. Proc. Am. Assoc. Cancer 185. STEWART,F. W. Experiences in Spontaneous Regression Research,3:72, 1959. of Neoplastic Disease in Man. Texas Rep. Biol. & Med., 204. WEBSTER, L. T. Inheritance of Resistance of Mice to 10:259â€”53, 1952. Enteric Bacterial and Neurotoxic Virus Infections. J. 186. SToci@a, P. Cancer Death Rates in Japan Contrasted Exper. Med., 65:261â€”86,1987. with Those in England and Wales and Canada. Brit. 205. WEILER, E. Antigenic Differences between Normal Ham J. Cancer, 10:257â€”64,1956. ster Kidney and Stilbesterol Induced Kidney Carcinoma; 187. S@roznuc,H. C., and EMERSON, G. A. Complete Regression Histologicel Demonstration by Means of Fluorescing of Lymphomosarcoma Implants after Temporary Induc Antibodies. Brit. J. Cancer, 10:560â€”68, 1956. tion of RIboflavin Deficiency in Mice. Proc. Soc. Exper. 206. WurrE, R. G. Discussion. Ford Hospital Symposium Biol.& Med., 70:703â€”4,1949. on Mechanism of Hypersensitivity, pp. 402-3, Boston: 188. STONE, H. B. ; CURTis, R. M.; and BREWER,J. H. Little, Brown & Co., 1959. Can Resistance to Cancer Be Induced? Ann. Surg., 207. Wissina, R. W.; BARKER, P. A.; Fi@tx, M. H.; LAVIA, 134:519â€”28,1951. M. F.; and TALMAGE,D.W. A Study of the Preparation, 189. STRONG, L. C. The Cumulative Effect of Litter Seriation Localization, and Effects of Antitumor Antibodies La on Fibrosarcoma Susceptibility in Mice. Ann. N.Y. Aced. beled with J131 Cancer Research, 16:761â€”74, 1956. @ Sc., 57:507â€”16, 1954. 208. WITEBSKY, E.; ROSE, N. R.; J. R.; and EGAN, 190. Suoiua@, K.; MOORE, A. E.; and S@oc@, C. C. Effect R. W. Thyroid-Specific Autoantibodies in Immunology of Aminopterin on the Growth of Carcinoma, Sarcoma and Cancer. Ann. N.Y. Aced. Sc., 69:669â€”77, 1957. and Melanoma in Animals. Cancer,2:491â€”502,1949. 209. WITEBSKY,E.; RosE, N. R.; and SHuisw@, S. Studies of 191. Stmsatun, W. C., and Foa@ucun, A. G. Spontaneous Re Normal and Malignant Tissue Antigens. Cancer Re gression of Human Melanoma: Clinical and Experimental search, 16:831â€”42,1956. Studies. Cancer, 13:79â€”81,1960. 210. WooLoM, W. H. Immunity to Transplantable Tumors. 192. TAKEDA, K. On the Immunopathologicel Specificity of Cancer Research,4: 129â€”95,1929. Tumor Cells. Gann, 46:567â€”83,1955. 211. WooD, H. F.; DIAMOND,H. D.; CRAvun, L. F.; P@iun, 193. TANNENBAUM,A. Effects of Varying Caloric Intake upon E.; and EzaTzai, S. K. Determination of C-reactive Tumor Incidenceand Tumor Growth. Ann. N.Y. Acad. Protein in the Blood of Patients with Hodgkin's Disease. Sc., 49:5-18, 1947. Ann. Int. Med., 48:828-88, 1958. 194. TAYLOR, A. R.; Giu@aN, A.; and BRANDON, F. B. Com 212. WYNDER, E. L. Some Practical Aspects of Cancer Pre plement-Fixing Antigens in Neoplastic Tissue Extracts. vention. NewEng. J. Med., 246:492-508,538-46,573-82, Virology, 7:349â€”51, 1959. 1952. 195.THOMAS, L. Cortisoneand Infection.Ann.N.Y. Aced. 218. YooN, L. Eosinophils and Gastrointestinal Cancer. Am. Sc.,56:799â€”814,1953. J. Surg., 97: 195â€”200,1959. 196.ToolAN, H. W. TransplantableHuman NeoplasmsMain 214. YOUNGE,P. A.; HERTIG,A. T.; and ARMSTRONG,D. tained in Cortisone-treated Laboratory Animals: H.S. A Study of 185 CasesofCarcinoma in Situofthe Cervix #1; H.Ep. #1; H.Ep. #2; H.Ep. #3, and H.Emb.Rh. at the Free Hospital for Women. Am. J. Obst. & Gyn., #1. Cancer Research, 14:660-66, 1954. 58:867â€”95, 1949. 197. . The PotentialitiesofNormal CellsImplanted 215. Zsx, B., and SUR, K. M. Technique for Separation of inCortisonizedand/orX-radiatedHosts:GuestEditorial. Protein by Means of Agar-Gel Electrophoresis. Am. J. Ibid., 17:248â€”50, 1957. Chin. Path., 29:69â€”79,1958. 198. TooLAN, H. W., and WALLACE, R. A. The Relative 216. ZILBER,L. A. Studies on Tumor Antigens. J. Nat. Cancer Ability of Cell-free Fractions of the Transplantable Hu Inst., 18:341â€”58, 1957. man Tumor H.Ep. #3 To Produce H.Ep. #3 Cytotoxins 217. .SpecificTumorAntigens.Adv.Cancer Research, in Rats. Cancer Research, 18:698â€”705,1958. 5:291â€”382, 1958. 199. Tirmrrni, J. J. Induced Tolerance and â€œHomologous218. ZILBER,L. A.; K.RIUKOVA,I.N.; Nasrrssssov, N. V.; Diseaseâ€•in X-irradiated Mice Protected with Homol and BnuimmA,'T. I. The SerologicalDifferentiation of ogous Bone Marrow. Proc. Soc. Exper. Biol. & Med., Extracts of Rous Sarcoma and Normal Tissue. Problems 96:139â€”44, 1957. of Oncology, 4:285â€”87,1958.

Chester M. Southam

Cancer Res 1960;20:271-291.

Updated version Access the most recent version of this article at: http://cancerres.aacrjournals.org/content/20/3_Part_1/271.citation

E-mail alerts Sign up to receive free email-alerts related to this article or journal.

Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Subscriptions Department at [email protected].

Permissions To request permission to re-use all or part of this article, use this link http://cancerres.aacrjournals.org/content/20/3_Part_1/271.citation. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site.