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Immunotherapy

Contributed by: June Kan-Mitchell, Malcolm S. Mitchell

Publication year: 2014

The treatment of by improving the ability of a tumor-bearing individual (the host) to reject the tumor immunologically. There are molecules on the surface of tumor cells, and perhaps in their interior, that are recognized as different from normal structures by the and thus generate an . These molecules, called tumor-associated antigens, have been clearly demonstrated with animal tumors and are strongly suggested with human tumors.

The two components of the immune response are cell-mediated and -mediated immunity, which must work in concert to overcome tumor cells. One type of thymus-derived lymphocyte (also called a ) can destroy tumor cells directly, while another recruits other white blood cells, the macrophages, that do the killing. Natural killer cells and perhaps other white blood cells may also participate. produced in reaction to a tumor probably work mostly by binding to white blood cells at one end and to tumor cells at the other, bringing the two cells into close proximity and facilitating destruction of the tumor cells. However, elements that normally regulate immunity, such as suppressor T cells, are stimulated excessively by the tumor, which leads to an immune response that is deficient and unable to reject the growing tumor. Thus the strategy of is to stimulate within or transfer to the tumor-bearing individual the appropriate antitumor elements while avoiding further stimulation of suppressor elements. See also: CELLULAR ; IMMUNOLOGIC

CYTOTOXICITY ; IMMUNOSUPPRESSION .

There are four broad categories of immunotherapy: active, adoptive, passive, and restorative.

Active immunotherapy

This form of treatment attempts to stimulate the host’s intrinsic immune response to the tumor, either nonspecifically or specifically.

Nonspecific. Nonspecific active immunotherapy utilizes materials that have no apparent antigenic relationship to the tumor, but have modulatory effects on the immune system, stimulating macrophages, lymphocytes, and natural killer cells. A large and rather heterogeneous group of agents have been studied, the best-known of which are microbial agents, such as bacillus Calmette-Gu erin´ (BCG), and also pyran, , and the vitamin A derivatives called retinoids. AccessScience from McGraw-Hill Education Page 2 of 4 www.accessscience.com

Clinical trials with nonspecific active immunotherapy alone have largely failed to improve the survival of cancer patients, with only a few exceptions, such as in nodular lymphoma and in ovarian cancer. Interferon-alpha is a low-molecular-weight protein produced by leukocytes in response to viral infection. Initial studies with partially purified, extracted interferon-alpha reported several remissions in patients with multiple myeloma and nodular, poorly differentiated lymphocytic lymphoma, and a prolonged survival of patients with osteosarcoma which was treated prophylactically after amputation. Partial responses were also observed in late-stage breast cancer patients. Trials of recombinant interferon-alpha have noted significant responses of patients with renal cell

(kidney) carcinoma, multiple myeloma (a bone marrow tumor), and Kaposi’s sarcoma, a tumor often found in patients with acquired immune deficiency syndrome (AIDS). However, it is uncertain whether the nonspecific immunomodulatory effects of interferon were responsible, since interferon also has a direct antitumor effect.

Studies on retinoids were prompted by epidemiological data showing a decreased incidence of lung and bladder cancer by the high intake of vitamin A. While retinoids do augment the immune response, like interferon they have direct effects on neoplastic cells. Retinoids also promote the maturation of preneoplastic cells toward normal development. See also: ACQUIRED IMMUNE DEFICIENCY SYNDROME (AIDS) ; VITAMIN A .

Specific. Specific active immunotherapy attempts to stimulate specific antitumor responses with tumor-associated antigens as the immunizing materials. Tumor cells from the same patient or from another with the same type of tumor, irradiated or altered in tissue cultures to make them more antigenic, have been used to try to augment specific immunity. Also, the potential usefulness of antigenic extracts, both soluble and particulate, has been investigated in such dissimilar diseases as malignant melanoma (malignant skin mole) and lung cancer. Rapid progress in identifying important tumor-associated antigens has been made with these and several other tumors, especially through the use of monoclonal antitumor antibodies. The use of extracts of tumor antigens for immunotherapy must be approached with great caution, since soluble tumor antigens can generate suppressor T cells when combined with a small amount of host antibodies. This could lead to enhanced tumor growth. The content of antigens in specific tumor , the form in which antigens should be presented to the patient (for example, particulate, together with adjuvant materials, and so on), and the schedule and route of administration are all critical questions. See also: MONOCLONAL ANTIBODIES .

Adoptive immunotherapy

This denotes the transfer of immunologically competent white blood cells or their precursors into the host. Bone marrow transplantation, while performed principally for the replacement of hematopoietic stem cells, can also be viewed as adoptive immunotherapy. Some success in the treatment of acute leukemia has been noted by allogeneic (second-party) bone marrow transplantation after sublethal irradiation of the patient. The results from syngeneic (twin) bone marrow transplants have been less encouraging, perhaps because the identical twin’s lymphocytes do not recognize the leukemic cells as sufficiently different from self to reject them. It is, however, possible to grow T cells in tissue culture with the aid of T-cell growth factor (-2), stimulate (or restimulate) them with tumor antigens, and transfuse the cells into the patient. This has been effective therapy in AccessScience from McGraw-Hill Education Page 3 of 4 www.accessscience.com

mice. Transfusion of leukocytes armed with antitumor antibodies is another approach that appears feasible for the treatment of human .

Restorative immunotherapy

This approach comprises the direct and indirect restoration of deficient immunological function through any means other than the direct transfer of cells. Repletion of competent effector-cell populations is one form of restorative immunotherapy. Thymic hormones, such as thymopoietin and thymosin, can convert T-cell precursors into helper T cells, a property shared by the antihelminthic agent Levamisole and several of its congeners. In a study of small-cell carcinoma of the lung, thymosin increased the median survival of patients who had sustained a complete response from chemotherapy. The subgroup that benefited most was the one with a deficient complement of T cells. Deficient functioning of T cells may be a problem in most patients with a tumor.

Deficient percentages of T cells relative to other leukocytes have been noted in several types of tumor, the most noteworthy of which is Kaposi’s sarcoma. Repletion of number or function is an important strategy which might by itself be curative in certain tumors. Antagonism of suppressor influences is another form of restorative therapy. Low doses of the antitumor drug cyclophosphamide selectively inhibit suppressor T cells. Inhibitors of prostaglandin synthesis, such as indomethacin, may be useful in overcoming other suppressor cells of the macrophage series, which act principally through prostaglandins. See also: EICOSANOIDS .

Passive immunotherapy

This means the transfer of antibodies to tumor-bearing recipients. This approach has been made feasible by the development of hybridoma technology, which now permits the production of large quantities of monoclonal antibodies specific for an antigenic determinant on tumor cells. Monoclonal antibodies made against tumor-specific antigens, if they in fact exist, or against tumor-associated antigens, which may be shared by certain normal cells, are of potential importance therapeutically. These antibodies probably work through the arming of white blood cells, especially macrophages, of the host. They may be most effective in treating dispersed tumors such as leukemia, and ovarian cancer in ascites (abnormal accumulation of serous fluid in the abdominal cavity).

The potential for enhancement of tumor growth, as a result of the formation of antigen-antibody complexes and the excessive stimulation of suppressor cells, exists and must be carefully monitored. The development of human monoclonals should obviate some of the allergic reactions that have occurred with mouse antibodies, and promises still greater specificity of attack on tumor cells. See also: CANCER (MEDICINE) ; GENETIC ENGINEERING ;

IMMUNOLOGY .

June Kan-Mitchell, Malcolm S. Mitchell

Bibliography

P. Calabresi and P. S. Schein (eds.), Medical Oncology: Basic Principles and Clinical Management of Cancer , 2d ed., 1993 AccessScience from McGraw-Hill Education Page 4 of 4 www.accessscience.com

S. Cryz, Immunotherapy and Intravenous Immunoglobulins , 1991

T. J. Hamblin, Immunotherapy and Disease , 1990

P. Imbach (ed.), Immunotherapy with Intravenous Immunoglobulins , 1991

M. S. Mitchell, The advent of monoclonal antibodies, Consultant , 23:127–134, 1983

Additional Readings

B. Kaplan, G. J. Burkhart, and F. G. Lakkis (eds.), Immunotherapy in Transplantation: Principles and Practice ,

John Wiley & Sons, Chichester, West Sussex, UK, 2012

J. Medin and D. Fowler (eds.), Experimental and Applied Immunotherapy , Springer Science+Business Media,

New York, 2011

N. P. Restifo, M. E. Dudley, and S. A. Rosenberg, Adoptive immunotherapy for cancer: Harnessing the T cell response, Nat. Rev. Immunol. , 12(4):269–281, 2012 DOI: http://doi.org/10.1038/nri3191