Abstract
The initial attempts to alter the progression of neoplastic diseases in patients with certain types of cancer through the application of maximally tolerated doses of cytotoxic agents took place 40 to 50 years ago. Since that time impressive successes have been achieved in a number of malignancies. Nevertheless, there remain frequently occurring neoplasms for which there is no curative treatment. The failures are related mainly to the fact that the agents available to date are not sufficiently selective in their antitumor action; therefore, even a relatively small degree of natural or acquired resistance cannot be overcome by dose escalation without incurring unacceptable toxicity. Although the search for new cytotoxic agents with improved antitumor selectivity is continuing, alternative therapeutic approaches are also being aggressively sought in several different directions. As an example, the increasing knowledge of the molecular mechanisms regulating the cancer cell provides new sites for which it should be possible to rationally design new agents with unique anticancer specificities. Likewise, based on information about the interactions between tumor and host, approaches that exploit both the immunological and the nonimmunological phenomena involved in these interactions are being tested. This chapter is concerned with the possibility of exploiting antitumor host defenses of the immunological type through the action of anticancer agents capable of inducting therapeutically favorable immunomodulation.
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References
Acerbis, G., Cleris, L., Rodolfo, M., Parmiani, G., and Formelli, F., 1992, Post surgical adjuvant chemoimmunotherapy with recombinant interleukin-2 and l, 3-bis-(2-chloroethyl)-1-nitrosurea on spontaneous metastases of a non-immunogenic murine tumour, Cancer Immunol Immunother.34: 383–388.
Afonso, L. C. C., Scharton, T. M., Vieira, L. Q., Wysocka, M., Trinchieri, G., and Scott, P., 1994, The adjuvant effect of interleukin-2 in a vaccine against Leishmania major, Science 263: 235–237.
Allavena, P., Pirovano, P., Bonazzi, C., Colombo, N., Mantovani, A., and D’lnacalci, M., 1990, In vitro and in vivo effects of cisplatin on the generation of lymphokine-activated killer cells, J. Natl Cancer Inst.82: 139–142.
Allison, J. P. 1993, γδ T-cell development, Curr. Opin. Immunol.5: 241–246.
Arinaga, S., Akiyoshi, T., and Tsuji, H., 1985, Augmentation of the cell-mediated cytotoxic response induced in mixed cell culture by adriamycin, Jpn. J. Cancer Res.76: 414–419.
Arinaga, S., Akiyoshi, T., and Tsuji, H., 1986, Augmentation of the generation of cell mediated cytotoxicity after a single dose of adriamycin in cancer patients, Cancer Res.46: 4213–4216.
Askenase, P. W., Hayden, B. J., and Gershon, R. K., 1975, Augmentation of delayed-type hypersensitivity by doses of cyclophosphamide which do not affect antibody responses, J. Exp. Med.141: 697–703.
Awwad, M., and North, R. J., 1989, Cyclophosphamide-induced immunologically mediated regression of a cyclophosphamide resistant murine tumor: A consequence of eliminating precursor L3T4+ suppressor T-cells, Cancer Res.49: 1649–1654.
Berd, D., Maguire, H. C., Jr., and Mastrangelo, M. J., 1986, Induction of cell-mediated immunity to autologous melanoma cells and regression of metastases after treatment with a melanoma cell vaccine preceded by cyclophosphamide, Cancer Res.46: 2572–2576.
Berd, D., Maguire, H. C., Jr., McCue, P., and Mastrangelo, M. J., 1990, Treatment of metastatic melanoma with an autologous tumor cell vaccine: Clinical and immunological results in 64 patients, J. Clin. Oncol.8: 1858–1867.
Berd, D., Murphy, G., Maguire, H. C., Jr., and Mastrangelo, M. J., 1991, Immunization with haptenized autologous tumor cells induces inflammation of human melanoma metastases, Cancer Res.51: 2731–2736.
Berd, D., Maguire, H. C., Jr., Mastrangelo, M. J., and Murphy, G., 1994a, Activation markers on T cells infiltrating melanoma metastases after therapy with dinitrophenyl-conjugated vaccine, Cancer Immunol Immunother.39: 141–147.
Berd, D., Sato, T., Lattime, E. C., Maguire, H. C., Jr., and Mastrangelo, M. J., 1994b, Immunization with hapten-modified tumor cells: A strategy for the treatment of human melanoma, Proc. AACR.35: 667–668.
Boon, T., Cerottini, J.-C., Van den Eynde, B., van der Bruggen, P., and Van Pel, A., 1994, Tumor antigens recognized by T lymphocytes, Annu. Rev. Immunol.12: 337–365.
Boyd, R. L., and Hugo, P., 1991, Towards an integrated view of thymopoiesis, Immunol. Today 12: 71–79.
Braun, D., and Harris, J. E., 1981, Modulation of the immune response by chemotherapy, Pharmacol Ther.14: 89–122.
Burton, D. R., and Barbas, C. F., III, 1994, Human antibodies from combinatorial libraries, Adv. Immunol.57: 191–280.
Chang, M.-J., Yu, W.-D., Reyno, L. M., Modzelewski, R. A., Egorin, M. J., Erkmen, K., Vlock, D. R., Furmnaski, P., and Johnson, C. S., 1994, Potentiation by interleukin la of cisplatin and carboplatin antitumor activity: Schedule-dependent and pharmokinetic effects in the RIF-1 tumor model, Cancer Res.54: 5380–5386.
Chuang, L. T., Lotzova, E., Heath, J., Cook, K. R., Munkarah, A., Morris, M., and Wharton, J. T., 1994, Alteration of lymphocyte microtubule assembly, cytotoxicity, and activation by the anticancer drug taxol, Cancer Res.54: 1286–1291.
Claessen, A. M. E., Valster, H., Bril, H., Meyer, S., and Scheper, R. J., 1989, Cell-mediated immunity is enhanced by cytostatic drugs continuously released at the site of antigenic stimulation, Cancer Immunol. Immunother.28: 131–135.
Clamon, G., Herndon, J., Perry, M. C., Ozer, H., Kreisman, H., Maher, T., Ellerton, J., and Green, M. R., 1993, Interleukin-2 activity in patients with extensive small-cell lung cancer: A phase II trial of Cancer and Leukemia Group B, J. Natl Cancer Inst.85: 316–320.
Colvin, M., Padgett, A. C., and Fenselou, C., 1973, A biologically active metabolite of cyclophosphamide, Cancer Res.33: 915–922.
Conran, P. B., and Rosenberg, B., 1972, The role of host defense in the regression of sarcoma-180 in mice treated with cis-dichlorodiammineplatinum(II), in: Antimicrobial and Antineoplastic Chemotherapy (M. Semonsky, M. Hejzlar, and S. Masai, eds.), University Park Press, New York, pp. 235–236.
Cowens, J. W., Ozer, H., Ehrke, M. J., Colvin, M., and Mihich, E., 1983, Inhibition of the development of suppressor cells in culture by 4-hydroperoxycyclophosphamide, J. Immunol.132: 95–100.
D’Atri, S., Tricarico, M., Margison, G.P., Allegrucci, M., Fuschiotti, P., Grohman, U., Giglietti, S., and Bonmassar, E., 1989, Antigenic changes of cancer cells following interaction with antitumour agents, in: Drug Resistance: Mechanisms and Reversal. (E. Mihich, ed.), John Libbey and Co., Rome, pp.271–294.
Diamanstein, T., Klos, M., Hahn, H., and Kaufmann, S. H. E., 1981, Direct in vitro evidence for different susceptibilities to 4-hydroperoxycyclophosphamide of antigen-primed T cells regulating humoral and cell-mediated immune responses to sheep erythrocytes, J. Immunol.126: 1717–1722.
Ding, A. H., Porteu, E, Sanchez, E., and Nathan, C. F., 1990, Shared actions of endotoxin and taxol on TNF receptors and TNF release, Science 248: 370–372.
Ehrke, M. J., 1991, Effect of cancer therapy on host response and immunobiology, Current Opin. Oncol 3: 1070–1077.
Ehrke, M. J., and Mihich, E., 1985, Immunoregulation by cancer chemotherapeutic agents, in: The Reticuloendothelial System: A Comprehensive Treatise, Volume VIII (J. W. Hadden and A. Szentivanyi, eds.), Plenum Press, New York, pp.309–347.
Ehrke, M. J., Tomazic, V., Ryoyama, K., Cohen, S. A., and Mihich, E., 1983, Adriamycin induced immunomodulation: Dependence upon time of administration, Int. J. Immunopharmacol.5: 43–48.
Ehrke, M. J., Maccubbin, D., Ryoyama, K., Cohen, S. A., and Mihich, E., 1986, Correlation between adriamycin-induced augmentation of interleukin 2 production and of cell mediated cytotoxicity, Cancer Res.46: 54–60.
Ehrke, M. J., Mihich, E., Berd, D., and Mastrangelo, M. J., 1989, Effects of anticancer agents on the immune system in man, Semin. Oncol.16: 230–253.
Ehrke, M. J., Krawczyk, C., Maccubbin, D., and Mihich, E., 1991, Therapeutic efficacy of cyclophosphamide (CY) and TNF therapy in a murine tumor model: Possible role of specific thymic CTL activity, Third Int. Workshop on Cytokines 3: 488.
Ehrke, M. J., Verstovšek, S., Krawczyk, C. M., Ujházy, P., Zaleskis, G., Maccubbin, D., and Mihich, E., 1995, Cyclophosphamide plus tumor necrosis factor-α chemoimmunotherapy cured mice: Life-long immunity and rejection of re-implanted primary lymphoma, Int. J. Cancer 63: 463–471.
Engelhard, V. H., 1994, Structure of peptides associated with class I and class II MHC molecules, Annu. Rev. Immunol.12: 181–207.
Farone, A. L., and Cox, D. C., 1992, 1, 3-bis(2-chloroethyl)-1-nitrosurea (BCNU)/interleukin-2 chemoimmunotherapy of murine L1210 leukemia, Cancer Immunol. Immunother.34: 279–281.
Ferrua, B., Manie, S., Doglio, A., Shaw, A., Sonthonnax, S., Limouse, M., and Schaffar, L., 1990, Stimulation of human interleukin 1 production and specific mRNA expression by microtubuledisrupting drugs, Cell Immunol.131: 391–397.
Fitch, F. W., McKisic, M. D., Lancki, D. W., and Gajewski, T. F., 1993, Differential regulation of murine lymphocyte subsets, Annu. Rev. Immunol.11: 29–48.
Furukawa, T., Kubota, T., Watanabe, M., Kuo, T.-H., Kase, S., Saikawa, Y., Tanino, H., Teramoto, T., Ishibiki, K., Kitajima, M., and Hoffman, R. M., 1993, Immunochemotherapy prevents human colon cancer metastases after orthotopic onplantation of histologically-intact tumor tissue in nude mice, Anticancer Res.13: 287–292.
Gautam, S. C., Chikkala, N. F., Ganapathi, R., and Hamilton, T. A., 1991, Combination therapy with adriamycin and interleukin 2 augments immunity against murine renal cell carcinoma, Cancer Res.51: 6133–6137.
Gorelik, L., Prokhorova, A., and Mokyr, M. B., 1994, Low-dose melphalan-induced shift in the production of a Th2-type cytokine to a Thl-type cytokine in mice bearing a large MOPC-315 tumor, Cancer Immunol. Immunother.39: 117–126.
Greenberg, P. D., 1991, Adoptive T cell therapy of tumors: Mechanisms operative in the recognition and elimination of tumor cells, Adv. Immunol.49: 281–355.
Gurtoo, H. L., Dahms, R. P., Kanter, P., and Vaught, J. B., 1978, Association and dissociation of the Ah locus with the metabolism of aflatoxin B1 by mouse liver, J. Biol Chem.253: 3952–3961.
Hammerling, G. J., Schonrich, G., Ferber, I., and Arnold, B., 1993, Peripheral tolerance as a multi-step mechanism, Immunol. Rev.133: 93–104.
Hawkins, M. M., Kingston, J. E., and Kinnier Wilson, L. M., 1990, Late deaths after treatment for childhood cancer, Arch. Dis. Child.65: 1356–1363.
Ho, R. L. X., Maccubbin, D., Ujhazy, P., Zaleskis, G., Eppolito, C., Mihich, E., and Ehrke, M. J., 1993a, Immunological responses critical to the therapeutic effects of adriamycin plus interleukin 2 in C57BL/6 mice bearing syngeneic EL4 lymphoma, Oncol Res.5: 363–372.
Ho, R. L. X., Maccubbin, D., Zaleskis, G., Krawczyk, C., Wing, K., Mihich, E., and Ehrke, M. J., 1993b, Development of a non-toxic adriamycin plus interleukin 2 therapy effective against both adriamycin sensitive and resistant lymphomas, Oncol Res.5: 373–381.
Huber, S. A. and Moraska, A., 1992, Cytolytic T lymphocytes and antibodies to myocytes in adriamycintreated BALB/c mice, Am. J. Path.140: 233–242.
Itohara, S., Mombaerts, P., Lafaille, J., Iacomini, J., Nelson, A., Clarke, A. R., Hooper, M. L., Farr, A., and Tonegawa, S., 1993, T cell receptor 8 gene mutant mice: Independent generation of αβ T cells and programmed rearrangements of γδ TCR genes, Cell 72: 337–348.
Jenkins, M. K., Schwartz, R. H., and Pardoll, D. M., 1988, Effects of cyclosporin A on T cell development and clonal deletion, Science 241: 1655–1658.
Katz, J. D., Lebow, L. T., and Bonavida, B., 1989, The in vivo depletion of Vβ17a+ T cells results in the inhibition of reticulum cell sarcoma growth in SJL/J mice, J. Immunol.143: 1387–1394.
Klein, H. O., Golbach, G., Voigt, P., Coerper, C., and Bernhardt, C., 1991, Combination of interferons and cytostatic drugs for treatment of advanced colorectal cancer, J. Cancer. Res. Clin. Oncol.117(Suppl. IV): S214-S220.
Krawczyk, C. M., Verstovšek, S., Ujházy, P., Maccubbin, D., and Ehrke, M. J., 1995, Protective immunity induced by cyclophosphamide plus TNF-a combination treatment of EL4 lymphoma-bearing C57BL/6 mice, Cancer Immunol. Immunother.40: 347–357.
Laude, M., Russo, K. L., Mokyr, M. B., and Dray, S., 1993, Cure of mice bearing a late-stage, highly metastatic, drug-resistant tumor by adoptive chemoimmunotherapy, Cancer Immunol. Immunother.36: 229–236.
LoRusso, P.M., Aukerman, S. L., Polin, L., Redman, B. G., Valdivieso, M., Biernat, L., and Corbett, L. H., 1990, Antitumor efficacy of interleukin-2 alone and in combination with adriamycin and dacarbazine in murine solid tumor systems, Cancer Res.50: 5876–5882.
Maccubbin, D., Mace, K., Ehrke, M. J., and Mihich, E., 1989, Modification of host antitumor defense mechanisms in mice by progressively growing tumor, Cancer Res.49: 4216–4224.
Maccubbin, D., Wing, K., Mace, K., Ho, R. L. X., Ehrke, M. J., and Mihich, E., 1992, Adriamycinmodulation of host defenses in tumor bearing mice, Cancer Res.52: 3572–3576.
McPhee, D., Pye, J., and Shortman, K., 1979, The differentiation of T lymphocytes: V. Evidence for intrathymic death of most thymocytes, Thymus 1: 151–159.
Manie, S., Schmid-Alliana, A., Kubar, J., Ferrua, B., and Rossi, B., 1993, Disruption of microtubule network in human monocytes induces expression of interleukin-1 but not that of interleukin-6 nor tumor necrosis factor-α, J. Biol Chem.268: 13675–13681.
Matzinger, P., 1993, Why positive selection? Immunol Rev.135: 81–131.
Matzinger, P., 1994, Tolerance, danger, and the extended family, Annu. Rev. Immunol.12: 991–1045.
Mihich, E., 1969, Modification of tumor regression by immunologic means, Cancer Res.29: 2345–2350.
Mihich, E., 1971, Preclinical evaluation of the interrelationships between cancer chemotherapy and immunity, in: Prediction of Response in Cancer Therapy (T. C. Hall, ed.), Natl. Cancer Inst. Monogr. No. 34, pp.90–102.
Mihich, E., and Ehrke, M. J., 1991, Immunomodulation by anticancer drugs, in: Biologic Therapy of Cancer: Principles and Practice (V. T. DeVita, Jr., S. Hellman, and S. A. Rosenberg, eds.), Lippincott, Philadelphia, pp.776–786.
Mihich, E., and Fefer, A., 1983, Biological Response Modifiers: Subcommittee Report, Natl. Cancer Inst. Monogr. No. 63, U.S. Government Printing Office, Washington, DC.
Mokyr, M. B., Hengst, J. C. D., and Dray, S., 1982, The role of antitumor immunity in cyclophosphamideinduced rejection of subcutaneous non-palpable MOPC-315 tumors, Cancer Res.42: 974–979.
Mokyr, M. B., Rubin, M., Newell, K. A., Prokhorova, A., and Bluestone, J. A., 1993, Involvement of TCR-V beta 8.3+ cells in the cure of mice bearing a large MOPC-315 tumor by low dose melphalan, J. Immunol.151: 4838–4846.
Mokyr, M. B., Prokhorova, A., Rubin, M., and Bluestone, J. A., 1994, Insight into the mechanism of TCR-V beta 8+/CD8+ T cell-mediated MOPC-315 tumor eradication, J. Immunol.153: 3123–3134.
Mosmann, T. R., and Coffman, R. L., 1989, Thl and Th2 cells: Different patterns of lymphokine secretion lead to different functional properties, Annu. Rev. Immunol.7: 145–173.
Nagarkatti, M., Nagarkatti, P. S., and Kaplan, A. M., 1988, Differential effect of BCNU on T cell, macrophage, natural killer and lymphokine-activated killer cell activities in mice bearing a syngeneic tumor, Cancer Immunol. Immunother. 27: 38–46.
Nagarkatti, M., Clary, S. R., and Nagarkatti, P. S., 1990, Characterization of tumor infiltrating CD4+ T cells as Thl cells based on lymphokine secretion and functional properties, J. Immunol.144: 4898–4904.
North, R. J., and Awwad, M., 1990, Elimination of cycling CD4+ suppressor T cells with an anti-mitotic drug releases non-cycling CD8+ T cells to cause regression of an advanced lymphoma, Immunol.71: 90–95.
O’Garra, A., and Murphy, K., 1994, Role of cytokines in determining T-lymphocyte function, Curr. Opin. Immunol.6: 458–466.
Oka, M., Hazama, S., Yoshino, S., Shimoda, K., Suzuki, M., Shimizu, R., Yano, K., Nishida, M., and Suzuki, T., 1994, Intraarterial combined immunochemotherapy for unresectable hepatocellular carcinoma: Preliminary results, Cancer Immunol. Immunother.38: 194–200.
Ozer, H., Cowens, J. W., Colvin, M., Nussbaum-Blumenson, A., and Sheedy, D., 1982, In vitro effect of 4-hydroperoxycyclophosphamide on human immunoregulatory T subset function, J. Exp. Med.155: 276–281.
Paciucci, P. A., Bekesi, J. G., Ryder, J. S., Odchimar, R., Chahinian, P. A., and Holland, J. F., 1991, Immunotherapy with IL2 by constant infusion and weekly doxorubicin, Am. J. Clin. Oncol.14: 341–348.
Robey, E., and Fowlkes, B. J., 1994, Selective events in T cell development, Annu. Rev. Immunol.12: 675–705.
Romagnani, S., and Maggi, E., 1994, Thl versus Th2 responses in AIDS, Curr. Opin. Immunol.4: 616–622.
Rubin, M., Bluestone, J. A., Newell, K. A., Prokhorova, A., and Mokyr, M. B., 1994, Cooperation between staphylococcal enterotoxin B and low dose melphalan in the cure of mice bearing a large MOPC-315 tumor and extensive metastases, J. Immunol.152: 3522–3529.
Ryoyama, K., Mace, K., Ehrke, M. J., and Mihich, E., 1982, The differential sensitivity of T-cell immune functions to vincristine and vinblastine, Int. J. Immunopharmacol.4: 187–194.
Salup, R. R., Back, T. C., and Wiltrout, R. H., 1987, Successful treatment of advanced murine renal cell cancer by bicompartmental adoptive chemoimmunotherapy, J. Immunol.138: 641–647.
Schwartz, A., Askenase, P. W., and Gershon, R. K., 1978, Regulation of delayed-type hypersensitivity reactions by cyclophosphamide-sensitive cells, J. Immunol.121: 1573–1579.
Selvan, R. S., Nagarkatti, P. S., and Nagarkatti, M., 1990, Role of IL-2, IL-4 and IL-6 in the growth and differentiation of tumor-specific CD4+ T helper and CD8+ T cytotoxic cells, Int. J. Cancer 45: 1096–1102.
Simon, J. C., Cruz, P. D., Bergstresser, P. R., and Tigelaar, R. E., 1990, Low dose ultraviolet B-irradiated Langerhans cells preferentially activate CD4+ cells of the T helper 2 subset, J. Immunol.145: 2087–2091.
Smith, J. J., Mihich, E., and Ozer, H., 1987, In vitro effects of 4-hydroperoxycyclophosphamide on human immunoregulatory T subset function, Meth. Find. Exp. Clin. Pharm.9: 555–568.
Sykes, M., Abraham, V. S., Harty, M. W., and Pearson, D. A., 1993, IL-2 reduces graft-versus-host disease and preserves a graft-versus-leukemia effect by selectively inhibiting CD4+ T cell activity, J. Immunol.150: 197–205.
Tomazic, V., Ehrke, M. J., and Mihich, E., 1980, Modulation of the cytotoxic response against allogeneic tumor cells in culture by adriamycin, Cancer Res.40: 2748–2755.
Ujházy, P., Chen, Y., Fredericks, W., Ho, R., Baker, R., Mihich, E., and Ehrke, M. J., 1990, The relationship between multidrug resistance and tumor necrosis factor resistance in an EL4 cell line model, Cancer Commun. 2: 181–188.
Waldmann, T. A., 1992, Immune receptors: Targets for therapy of leukemia/lymphoma, autoimmune diseases and for the prevention of allograft rejection, Annu. Rev. Immunol.10: 675–704.
Weiskirch, L. M., Bar-Dagan, Y., and Mokyr, M. B., 1994, Transforming growth factor-beta-mediated down-regulation of antitumor cytotoxicity of spleen cells from MOPC-315 tumor-bearing mice engaged in tumor eradication following low-dose melphalan therapy, Cancer Immunol Immunother. 38: 215–224.
Yamamura, M., Modlin, R. L., Ohmen, J. D., and Moy, R. L., 1993, Local expression of antiinflammatory cytokines in cancer, J. Clin. Invest.91: 1005–1010.
Zaleskis, G., Berleth, E., Ehrke, M. J., and Mihich, E., 1994a, Doxorubicin induced DNA degradation in murine thymocytes, Mol Pharmacol.46: 901–908.
Zaleskis, G., Ehrke, M. J., Verstovsek, S., Tzai, T. S., and Mihich, E., 1994b, Doxorubicin and cyclosporin A exhibit opposite immunophenotype toxicity in hematopoietic cells, Proc. AACR 35: 389.
Zaleskis, G., Ho, R. L. X., Diegelman, P., Maccubbin, D., Ujhazy, P., Mihich, E., and Ehrke, M. J., 1994c, Intracellular doxorubicin kinetics in lymphoma cells and lymphocytes infiltrating the tumor area in vivo: A flow cytometric study, Oncol Res. 6: 183–194.
Zaleskis, G., Verstovsek, S., Tzai, T.-S., Mihich, E., and Ehrke, M. J., 1995, Doxorubicin and cyclosporin A affect murine lymphoid cell expressing different antigenic determinants, Oncol Res.7: 307–316.
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Ehrke, M.J., Mihich, E. (1996). Immunopharmacology of Anticancer Agents. In: Hadden, J.W., Szentivanyi, A. (eds) Immunopharmacology Reviews Volume 2. Springer, Boston, MA. https://doi.org/10.1007/978-1-4613-0349-7_4
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