- Email: [email protected]
Overview: Immunopharmacology as a new discipline
16. Renoux, G., and M. Renoux. 1981. Immunologic activity of DTC: potential for cancer therapy, p. 427. hz E. M. Hersh, M. A. Chirigos and M. J. Mastrangelo, (eds.), Progress in cancer research and therapy. Augmenting agents and cancer therapy. Raven Press, New York. 17. Serrou, B., et al. 1983. Phase I evaluation of Bestatin in patients bearing advanced solid tumors. In: M. D. Terry, (ed.), Immunotherapy of cancer. Present status of trials in man. Elsevier North Holland Publishing Co., Amsterdam (In press).
18. Suda~ H.~ et al. 1976. The chemical synthesis of Bestatin. J. Antibiot. 29:600. 19. Suda, II., et al. 1976. The structure of Bestatin. J. Antibiot. 29:600. 20. Umezawa, H. 1978. Small molecular microbial products enhancing immune responses. Antibiot. Chemother. 24:9. 21. Umezawa, H., et al. 1976. Bestatin, an inhibitor of aminopeptidase B, produces by actinomycetes. J. Antiblot. 29:97. 22. Umezawa, H., et al. 1976. Enhancement of delayed-type hypersensitivity by Bestatin, an inhibitor of
aminopeptidase B and leucine aminopeptidase. J. Antibiot. 29:857. 23. Yamakura, T., T. Shimbo, and J. Yata. 1981. Effects of an aminopeptidase inhibitor (Bestatin) on human lymphocytes. I. Effect on poke weed mitogen-induced in vitro immunoglobulin production, p. 109. bt: H. Umezawa (ed.), Small molecular immunomodifiers of microbial origin. Fundamental and clinical studies of Bestatin. Japan Scientific Societies Press, Pergamon Press, New York.
the notion that immunorestoration would be relevant therapy in cancer. The rationale for the development of a science of immunopharmacology unfortunately came later and followed on a decade of empirical efforts to treat cancer patients mainly with crude bacterial preparations. The frustration of this effort expressed in Dr. Reizenstein's contribution to this issue has led many to question the potential of this therapeutical venture. The lessons learned from it are not unanimously interpreted in the same way. My own view is that the first phase of effort in this area has yielded what might have been expected: a limited success in increasing survival in cancer patients which has resulted almost exclusively from increasing the number of patients who will remain in remission following extensive cytoreduction therapy with surgery, irradiation, or chemotherapy, i.e., we have found in man as we learned in animals that with spontaneous tumors of low antigenicity, the immune system offers little more than a clean-up operation for minimal residual tumor in hosts capable of mounting an immune response. This progress is not to be underestimated; there are a plethora of studies that document a degree of efficacy of immunotherapy in the major cancers which affect man. What is frustrating is the number of negative studies and the inability to predict who will benefit from such therapy. The recognition is emerging
that without a science of immunotherapy, that is an immunopharmacology, little hope exists for rational successful immunomanipulation. For many of us, this science is long overdue. Every engineering effort requires a drawing board and a set of tools and rules to make a testable plan of action which, when verified, can be translated into practice. For immunotherapy, this is needed but it does not mean returning to square one. A large body of sufficiently reliable data has been accumulated to form a basis for the field. We have learned much about immunodeficiency and cancer and its prognostic significance. It can now be stated axiomatically, as was predicted by surveillance notions, that the more immunologically competent you are the better you do with your cancer. We have learned that the sledgehammer approach with crude antigenic bacterial preparations carries unacceptable toxicity and ambivalent effects on the immune system. More selective and effective immunorestoration efforts are needed. In this regard a large number of biological substances such as the thymic hormones, interferons, and lymphokines have been intensively studied and introduced into experimental therapy with very encouraging results. More than 40 chemically derived drugs are under development, one of which is Bestatin, discussed in this issue by Blomgren. Virtually all of these agents
Guest Editorial
Overview: Immunopharmacology as a New Discipline John Hadden, M.D.
Program of bnnnmopharmacology University of South Florida College of Medicine Tampa, Florida 33612 Immunopharmacology is a new field of study which bridges the area between its two parental disciplines of immunology and pharmacology. Its focus is on the study of immunoregulation with a view toward its utility in the therapy of human disease. As a new field, immunopharmacology,s development has been marked by the appearance of three journals, each in their fourth year of publication, several textbooks, two international conferences (1980 and 1982), and an international society with membership in excess of 600 members. For the readers of the Clinical hnmunology Newsletter, I will attempt to briefly summarize the implications these developments have for clinical immunologists. * The primary rationale for the origins of immunotherapy derived from *For additional information and a more detailed review of the subject, the reader is referred to the article "Immunomodulators in the Immunotherapy of Cancer and Other Diseases" (Hadden, J. H., 1982. Trends in Pharmacologic Series, 3:191-194).
18
Clinical ImmunologyNewsletter
show immunopharmacologic characteristics which are improvements over levamisole, the most widely used chemically defined agent in cancer immunotherapy. Several classes of agents can be delineated; examples are: a) the sulfur-containing compounds, e.g., thiobenzimidazoles, diethyl dithiocarbamate, NPT 16416, and cimetidine; b) purines, e.g., isoprinosine, NPT 15392; c) substituted sugars, e.g., muramyl dipeptides (MDP); d) the glycans, e.g., lentinan, picibanil, krestin; e) nontoxic interferon inducers, e.g., pyran copolymer MVE-2, the 6-aryl pyrimidinoles; and f) miscellaneous, e.g., azimexon, Bestatin, tuftsin, etc. These agents have differing modes of action and offer in some cases a high degree of selectivity on their target cells. Other recent advances include the development of a) monoclonal antibodies already successfully employed alone in cancer therapy. Their arming with isotopes, enzymes, and toxins offers targeting potential by specific cytoreductive therapy; b) the use of lysosomes to target immunoreactive agents to the reticuloendothelial system and thus potentiate their action; c) the detoxification of endotoxin (LPS) with preservation of its anticancer activity mediated perhaps by tumor necrosis mechanisms; d) agents and strategies to overcome tumor-derived and immune system-derived suppressor mechanisms and finally, e) increasing knowledge of tumorassociated antigens and the adaption cancer-bearing patients have to these antigens as manifested by the high incidence of circulating antigen-antibody complexes. Already emphasis is being placed on the development of animal tumor
Journal
models that better reflect the human condition. Very notable are the recent demonstrations that immunotherapeutic agents can be employed with synergistic results: examples of effective combinations are isoprinosine and interferon, isoprinosine and NPT 15392, MDP and lymphokines, LPS and lymphokines, and LPS and cell wall skeleton. Collectively, the immunodiagnostic and therapeutic advances to date make it abundantly clear that immunotherapy will improve. The knowledge gleaned has reinforced the appreciation that such therapy in immunosuppressed, nutritionally compromised patients will be forever limited by the potential of the immune system of a particular patient for restoration. Active progressive terminal cancer will probably never be a situation for successful immunotherapy. However, therapy specifically designed for the type and extent of immunodeficiency in a particular patient and complementary efforts to direct the immune response to the cancer in ways that relate to rejection will surely improve on our curent level of therapeutic success. Not only will the patients remaining in remission increase, but also their tolerance to chemotherapy will be improved and the infectious complications will be prevented or better managed. As with the space effort, important spin-offs have derived from the development of immunodiagnostics and immunotherapy of cancer. The trends that led to documenting immunodeficiency in cancer have led to increasing definition of the prevalence of immunodeficiency in other disease states. It is now apparent that immunodeficiency exists in large seg-
ments of the world's population, i.e., in the malnourished, the parasiteinfested, and the aging, to name a few. New syndromes are being defined which have immunodeficiency as part of the pathogenesis, e.g., legionnaires disease, asbestos and polybrominated biphenyl toxic exposure syndromes, and acquired immunoregulatory disease. By far the most common sequelae of immunodeficiency are infections, not cancer. The development of immunotherapeutie agents has naturally resulted in their experimental use in infections, and a wide variety for infections have been studied. The successful use of interferon, muramyl dipeptides, transfer factor, and glucans both in prophylactic and therapeutic treatment of virus and bacterial challenge experiments in animals amply document their efficacy. The application of this "prohost" approach for treatment of infection in man has been heralded by effective clinical trails with interferon, isoprinosine, and to a lesser extent with levamisole. The notion is progressively emerging that having a defective immune system is a disease even before cancer or infection develop--much as hypertension or arteriosclerosis are diseases even before strokes or myocardial infarction result. The idea of treating immunodeficiency as a disease is as rational as that of treating cardiovascular disease. While futuristic for the clinical immunologist, the rapid growth of immunopharmacology predicts that the future will bring a variety of safe and selective biologicals and drugs for the treatment of a variety of human disorders ranging from cancer to aging, autoimmunity, and infection.
function. Two human T-cell hybridomas produced 6 0 - 8 0 % suppression of in vitro polyclonal immunoglobulin production when cocultured with PWM-stimulated peripheral blood lymphocytes. One of these hy-
bridomas secreted a soluble suppressor factor(s) which gave reversible noncytotoxic inhibition of lectin-activated B-cell Ig production. The technique of somatic cell fusion offers one approach to the study of human im-
Article Highlights
W. C. Greene et al. Production of human suppressor T cell hybridomas. J. Immunol. 129:1986, 1982. This paper describes the successful production of cloned human T-cell hybridomas with retained suppressor
© 1983 by Elsevier Science Publishing Co., Inc.
19
18. Suda~ H.~ et al. 1976. The chemical synthesis of Bestatin. J. Antibiot. 29:600. 19. Suda, II., et al. 1976. The structure of Bestatin. J. Antibiot. 29:600. 20. Umezawa, H. 1978. Small molecular microbial products enhancing immune responses. Antibiot. Chemother. 24:9. 21. Umezawa, H., et al. 1976. Bestatin, an inhibitor of aminopeptidase B, produces by actinomycetes. J. Antiblot. 29:97. 22. Umezawa, H., et al. 1976. Enhancement of delayed-type hypersensitivity by Bestatin, an inhibitor of
aminopeptidase B and leucine aminopeptidase. J. Antibiot. 29:857. 23. Yamakura, T., T. Shimbo, and J. Yata. 1981. Effects of an aminopeptidase inhibitor (Bestatin) on human lymphocytes. I. Effect on poke weed mitogen-induced in vitro immunoglobulin production, p. 109. bt: H. Umezawa (ed.), Small molecular immunomodifiers of microbial origin. Fundamental and clinical studies of Bestatin. Japan Scientific Societies Press, Pergamon Press, New York.
the notion that immunorestoration would be relevant therapy in cancer. The rationale for the development of a science of immunopharmacology unfortunately came later and followed on a decade of empirical efforts to treat cancer patients mainly with crude bacterial preparations. The frustration of this effort expressed in Dr. Reizenstein's contribution to this issue has led many to question the potential of this therapeutical venture. The lessons learned from it are not unanimously interpreted in the same way. My own view is that the first phase of effort in this area has yielded what might have been expected: a limited success in increasing survival in cancer patients which has resulted almost exclusively from increasing the number of patients who will remain in remission following extensive cytoreduction therapy with surgery, irradiation, or chemotherapy, i.e., we have found in man as we learned in animals that with spontaneous tumors of low antigenicity, the immune system offers little more than a clean-up operation for minimal residual tumor in hosts capable of mounting an immune response. This progress is not to be underestimated; there are a plethora of studies that document a degree of efficacy of immunotherapy in the major cancers which affect man. What is frustrating is the number of negative studies and the inability to predict who will benefit from such therapy. The recognition is emerging
that without a science of immunotherapy, that is an immunopharmacology, little hope exists for rational successful immunomanipulation. For many of us, this science is long overdue. Every engineering effort requires a drawing board and a set of tools and rules to make a testable plan of action which, when verified, can be translated into practice. For immunotherapy, this is needed but it does not mean returning to square one. A large body of sufficiently reliable data has been accumulated to form a basis for the field. We have learned much about immunodeficiency and cancer and its prognostic significance. It can now be stated axiomatically, as was predicted by surveillance notions, that the more immunologically competent you are the better you do with your cancer. We have learned that the sledgehammer approach with crude antigenic bacterial preparations carries unacceptable toxicity and ambivalent effects on the immune system. More selective and effective immunorestoration efforts are needed. In this regard a large number of biological substances such as the thymic hormones, interferons, and lymphokines have been intensively studied and introduced into experimental therapy with very encouraging results. More than 40 chemically derived drugs are under development, one of which is Bestatin, discussed in this issue by Blomgren. Virtually all of these agents
Guest Editorial
Overview: Immunopharmacology as a New Discipline John Hadden, M.D.
Program of bnnnmopharmacology University of South Florida College of Medicine Tampa, Florida 33612 Immunopharmacology is a new field of study which bridges the area between its two parental disciplines of immunology and pharmacology. Its focus is on the study of immunoregulation with a view toward its utility in the therapy of human disease. As a new field, immunopharmacology,s development has been marked by the appearance of three journals, each in their fourth year of publication, several textbooks, two international conferences (1980 and 1982), and an international society with membership in excess of 600 members. For the readers of the Clinical hnmunology Newsletter, I will attempt to briefly summarize the implications these developments have for clinical immunologists. * The primary rationale for the origins of immunotherapy derived from *For additional information and a more detailed review of the subject, the reader is referred to the article "Immunomodulators in the Immunotherapy of Cancer and Other Diseases" (Hadden, J. H., 1982. Trends in Pharmacologic Series, 3:191-194).
18
Clinical ImmunologyNewsletter
show immunopharmacologic characteristics which are improvements over levamisole, the most widely used chemically defined agent in cancer immunotherapy. Several classes of agents can be delineated; examples are: a) the sulfur-containing compounds, e.g., thiobenzimidazoles, diethyl dithiocarbamate, NPT 16416, and cimetidine; b) purines, e.g., isoprinosine, NPT 15392; c) substituted sugars, e.g., muramyl dipeptides (MDP); d) the glycans, e.g., lentinan, picibanil, krestin; e) nontoxic interferon inducers, e.g., pyran copolymer MVE-2, the 6-aryl pyrimidinoles; and f) miscellaneous, e.g., azimexon, Bestatin, tuftsin, etc. These agents have differing modes of action and offer in some cases a high degree of selectivity on their target cells. Other recent advances include the development of a) monoclonal antibodies already successfully employed alone in cancer therapy. Their arming with isotopes, enzymes, and toxins offers targeting potential by specific cytoreductive therapy; b) the use of lysosomes to target immunoreactive agents to the reticuloendothelial system and thus potentiate their action; c) the detoxification of endotoxin (LPS) with preservation of its anticancer activity mediated perhaps by tumor necrosis mechanisms; d) agents and strategies to overcome tumor-derived and immune system-derived suppressor mechanisms and finally, e) increasing knowledge of tumorassociated antigens and the adaption cancer-bearing patients have to these antigens as manifested by the high incidence of circulating antigen-antibody complexes. Already emphasis is being placed on the development of animal tumor
Journal
models that better reflect the human condition. Very notable are the recent demonstrations that immunotherapeutic agents can be employed with synergistic results: examples of effective combinations are isoprinosine and interferon, isoprinosine and NPT 15392, MDP and lymphokines, LPS and lymphokines, and LPS and cell wall skeleton. Collectively, the immunodiagnostic and therapeutic advances to date make it abundantly clear that immunotherapy will improve. The knowledge gleaned has reinforced the appreciation that such therapy in immunosuppressed, nutritionally compromised patients will be forever limited by the potential of the immune system of a particular patient for restoration. Active progressive terminal cancer will probably never be a situation for successful immunotherapy. However, therapy specifically designed for the type and extent of immunodeficiency in a particular patient and complementary efforts to direct the immune response to the cancer in ways that relate to rejection will surely improve on our curent level of therapeutic success. Not only will the patients remaining in remission increase, but also their tolerance to chemotherapy will be improved and the infectious complications will be prevented or better managed. As with the space effort, important spin-offs have derived from the development of immunodiagnostics and immunotherapy of cancer. The trends that led to documenting immunodeficiency in cancer have led to increasing definition of the prevalence of immunodeficiency in other disease states. It is now apparent that immunodeficiency exists in large seg-
ments of the world's population, i.e., in the malnourished, the parasiteinfested, and the aging, to name a few. New syndromes are being defined which have immunodeficiency as part of the pathogenesis, e.g., legionnaires disease, asbestos and polybrominated biphenyl toxic exposure syndromes, and acquired immunoregulatory disease. By far the most common sequelae of immunodeficiency are infections, not cancer. The development of immunotherapeutie agents has naturally resulted in their experimental use in infections, and a wide variety for infections have been studied. The successful use of interferon, muramyl dipeptides, transfer factor, and glucans both in prophylactic and therapeutic treatment of virus and bacterial challenge experiments in animals amply document their efficacy. The application of this "prohost" approach for treatment of infection in man has been heralded by effective clinical trails with interferon, isoprinosine, and to a lesser extent with levamisole. The notion is progressively emerging that having a defective immune system is a disease even before cancer or infection develop--much as hypertension or arteriosclerosis are diseases even before strokes or myocardial infarction result. The idea of treating immunodeficiency as a disease is as rational as that of treating cardiovascular disease. While futuristic for the clinical immunologist, the rapid growth of immunopharmacology predicts that the future will bring a variety of safe and selective biologicals and drugs for the treatment of a variety of human disorders ranging from cancer to aging, autoimmunity, and infection.
function. Two human T-cell hybridomas produced 6 0 - 8 0 % suppression of in vitro polyclonal immunoglobulin production when cocultured with PWM-stimulated peripheral blood lymphocytes. One of these hy-
bridomas secreted a soluble suppressor factor(s) which gave reversible noncytotoxic inhibition of lectin-activated B-cell Ig production. The technique of somatic cell fusion offers one approach to the study of human im-
Article Highlights
W. C. Greene et al. Production of human suppressor T cell hybridomas. J. Immunol. 129:1986, 1982. This paper describes the successful production of cloned human T-cell hybridomas with retained suppressor
© 1983 by Elsevier Science Publishing Co., Inc.
19