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Home , Chemotherapy, Immunosuppressive drug

[ RESEARCH 28, 1452-1454,July 1968] Are Immunosuppressive Anticancer Self-defeating?1

Robert S. Schwartz The Clinical Immunology Service, New England Medical Center Hospitals and Tujts University School of Medicine, Boston, Massachusetts

A substantial body of evidence indicates that tumors of ex doses of drugs are required. In addition to effects on circulat perimental animals, whether elicited by or viruses, ing formation, these agents depress cellular-immune possess neoantigens capable of provoking typical immune re (delayed hypersensitivity) responses. In the case of 6-MP this sponses. In many instances it appears that these type of immunity is more readily inhibited than IgG produc gain a foothold and finally prove lethal because they escape tion (6). The retention of allografts can be greatly prolonged detection or destruction by immune mechanisms. Whenever the by , 6-MP, and MTX and, when antigenic acquisition of immunity against tumor fails—because differences between donor and host are not strong, an even of either immunologie tolerance (29) or defective immuno greater effect is seen (37). logie surveillance (7)—neoplastic growth is favored. It may be An intriguing property of the immunosuppressive anticancer more than coincidence that carcinogens are among the most drugs is their capacity to condition an adult animal for the powerful immunosuppressive agents known (30), that onco- acquisition of specific immunologie tolerance. Tolerance of a genic viruses depress immune responses (32), and that the variety of antigens, including polypeptides (38), (35), immunosuppressive 6- (6-MP) is carci viruses (13), erythrocytes (2), and allografts (14), has been nogenic (9). In light of this, it seems paradoxical to treat can acquired by animals [and probably humans (22)] treated with cer with drugs that profoundly inhibit the very system con cyclophosphamide, 6-MP, or MTX. The tolerance is specific for sidered essential for protection against neoplastic cells. If an the administered during the period of can retard the rejection of a allograft, and closely resembles the form of immunologie tolerance why not the same effect with regard to an antigenic ? acquired by neonates. Prior sensitization does not preclude the It is, after all, only an accident of priorities that many drugs induction of tolerance of the sensitizing antigen by chemo are known as anticancer agents rather than immunosuppres- (21). Of singular importance is the observation—made sants. repeatedly—that only a relatively brief course of drug treat It is reasonable to inquire whether or not observations on ment is required to condition an animal for the induction of tumor immunity made in mice and chickens have any rele immunologie tolerance. vance to human neoplasms. All that can be said at present is There is every indication that the representative anticancer that the data are inadequate. There is, however, an important drugs mentioned before are immunosuppressive in man, clue revealed by certain types of immunologie deficiencies. In although the evidence concerning is not entirely these there is an abnormally high incidence of leu convincing. Studies carried out with cyclophosphamide, 6-MP, kemia and (12), which is at least consistent with 6-thioguanine, , MTX, or 5-fluoro-2'-deoxyuridine the notion that the growth of some human neoplasms is fa (FUDR) in either normal humans (23), patients with immu vored by defective immunity. A clearcut demonstration of nologie diseases (40), or cancer patients (16) demonstrated neoantigens in human neoplasms could provide a means to impaired responses to a variety of antigens, with primary and test the hypothesis that immunosuppressive anticancer drugs, secondary immune responses, delayed hypersensitivity, and by impairing the patient's immunity, might be self-defeating. skin allograft rejection being affected to one degree or another. Six types of chemicals—alkylating agents, analogs, The doses of drugs used in these experiments were those folie acid antagonists, halogenated , the generally employed in the treatment of neoplasms. As a rule, , and the corticosteroids—are the stock in trade of the weaker the antigenic stimulus, the greater was the cancer chemotherapists. Each of them very significantly de immunosuppressive effect of the drug under study. In instances presses the (10, 36). Each can completely when short-term (five days) chemotherapy was employed, inhibit the synthesis of circulating , especially when suppression of antibody synthesis lasted at least four weeks, at given close to the time of immunization. When only moderate which time the experiment was terminated (15). Preexisting doses of cyclophosphamide (33), 6-MP (31), or antibodies have been resistant to depression, except when high (MTX) (5) are given, antibodies are formed, but they are doses of were given (26). almost entirely of the IgM class. Thus, these drugs appear to A notable effect of the immunosuppressive drugs is inhibition inhibit IgG antibody synthesis in a selective manner. Pre of transplantation immunity. Indeed, the current practice of existing immunity can also be impaired, but, in general, large transplantation depends in large measure on the immunosuppressive properties of the purine analogs, such as i Supported by USPHS Grant AM 07937-04. 6-MP and azathioprine. Not only can immune responses to

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Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1968 American Association for Cancer Research. Immunosuppressive Drugs normal tissues be inhibited, but those to grafts of neoplasms rabbits failed to cause regression of tumors. A delayed can also be profoundly depressed. The pioneering work of hypersensitivity mechanism could be important in halting the Toolan (41, 42) demonstrated that cortisone treatment can spread of this neoplasm, and it is of some interest that MTX significantly prolong the survival of malignant xenografts and completely blocked delayed type reactions to the Shope fibroma allow the serial propagation of human tumors in cortisone- virus (3). Another possible example of enhancement of the treated hamsters, rats, and mice. Cortisone has similar effects growth of an autochthonous neoplasm by an immunosuppres- when allogeneic neoplasms (34) are used and, in some situa sive drug was recently disclosed (9). Newborn mice of the tions, also appears to promote widespread métastases(1). C57BL strain were given four injections of 6-MP and, after An illuminating series of experiments has been carried out a latent period of five months, 29% had developed a lymphoma. utilizing a transplantable , L1210, and its antifolic- The mechanism of this phenomenon is unknown and a number resistant variants. These neoplasms are rejected by allogeneic of possibilities will have to be considered; nevertheless, it is recipients in a manner typical of allografts. However, treat conceivable that the inhibitory effects of the antimetabolite ment of recipients of an antifolic-resistant leukemia with MTX on immunity was connected with the high incidence of neo resulted in progressive tumor growth and death (18). It was plasms in these animals. shown that inocula containing only very small numbers of It is naturally tempting to relate these findings in experi allogeneic tumor cells could evolve into lethal neoplasms in mental animals to the problem of cancer in man, but, however MTX-treated mice (19). It may be of some interest that the alluring this may be, any such analogies would not be degree of immune suppression necessary to permit the un supported by presently available data. By and large, experi restricted growth of this allogeneic neoplasm could be brought mentally induced neoplasms are well-defined, readily studied about by a dose of MTX which prolonged the survival of an systems; in comparison, spontaneous in man are allogeneic skin by only two days (11). MTX can also not understood at all. There is, for example, little convincing condition an adult animal so that it acquires immunologie evidence that immune mechanisms modulate the growth of tolerance of allogeneic neoplasms (43). The tolerance was human tumors, and until this is demonstrated it would be induced by a treatment consisting of MTX and a suspension unwise to leap to far-reaching conclusions regarding the of non-neoplastic allogeneic cells. Following this, the animals immunosuppressive properties of anticancer drugs. There is received tumor cells from the strain donating the initial also the fact that not all compounds with antitumor activity suspension of cells. When donor and recipient shared the same are immunosuppressive. mustard is a good example of H-2 alíele, 15/15 mice acquired specific tolerance of the this, since it does not inhibit antibody synthesis in the rat malignant graft. 6-MP has also been shown to abrogate when given doses sufficient to inhibit the growth of the immunity to tumor allografts in experimental animals (17), Walker 256 tumor (8). Furthermore, even though inhibition but, more seriously, the purine analog azathioprine has ap of immunity occurs in patients treated with these agents parently suppressed the rejection of allogeneic in man. there is usually a powerful antitumor effect as well. Thus, a These extraordinary cases involve the transplantation of an balance of forces must interplay: suppression of immunity ostensibly normal kidney removed from a patient who had and suppression of neoplastic growth. At least from the just died of cancer. In one instance, the donor had died of clinician's point of view, the second-named force is the bronchogenic and, five months later, a morpholog immediate observable effect which benefits his patient. ically identical tumor killed the recipient (24). In another Whether or not the immunosuppressive effect could be re case, the kidney was obtained from a donor with a carcinoma sponsible for the usual recurrence and continued growth of the of the pyriform sinus and, seven months later, the recipient neoplasm is simply unknown. All that can be done now is to died of the same neoplasm (25). provide a climate for considering the validity of the hypothesis Several experiments have been carried out in syngeneic mentioned earlier in the event that immune mechanisms are systems. Here, induced by 3-methylcholanthrene of demonstrated importance in determining the course of (MCA) were found to take with a higher frequency in mice human neoplasms. treated with either cyclophosphamide, MTX, or FUDR (27, 28). Operationally, MCA-induced sarcomas are allografts, REFERENCES since they possess individual-specific neoantigens and are usually rejected by syngeneic hosts. More interesting, perhaps, 1. 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Robert S. Schwartz

Cancer Res 1968;28:1452-1454.

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