In vivo evaluation of the effects of interleukins 2, 4 and 7 on enhancing the immunotherapeutic efficacy of anti-tumor cytotoxic T lymphocytes.
The draining lymph nodes of mice injected with viable syngeneic tumor cells contain lymphoid cells capable of generating anti-tumor cytotoxic T lymphocytes (CTL) during a 4-day in vitro culture period and intravenous infusion of relatively low numbers of these CTL can effectively eliminate a challenge of fibrosarcoma cells at distal skin sites that would otherwise result in the death of the host. Using this model system the effects of addition of interleukin (IL) 2, IL4 or IL7 to the culture medium on the therapeutic efficacy of the anti-tumor CTL generated was investigated. In this regard, IL7 was found to be the most potent of the cytokines tested. Addition of IL7 either alone, or in combination with low doses of IL2, resulted in the generation of CTL with significantly (6-8-fold) enhanced therapeutic efficacy in vivo. Anti-tumor effector cells generated in the presence of IL7 were also found to be at least 4-fold more effective at eliminating established tumors than CTL generated in medium alone. Of the other cytokines tested, addition of IL2 resulted in elevated CTL activity in vitro, but only a modest (approximately 2-3-fold) enhancement of the therapeutic efficacy in vivo. Addition of IL4, either alone or in combination with IL2, also resulted in the generation of effector cells with enhanced tumoricidal activity in vitro and yet the therapeutic efficacy of these cells was decreased compared to that of CTL generated in medium alone. These observations indicate that (a) inclusion of IL7 in the medium in which tumor-reactive T cells are cultured can markedly enhance the immunotherapeutic efficacy of the resulting effector cell populations; and (b) in vitro assays of tumoricidal activity cannot be used as a reliable predictor of therapeutic efficacy in vivo.
Department of Immunology, Immunex Corporation, Seattle, WA 98101.
D H
DH
Lynch
A E
AE
Namen
R E
RE
Miller
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D000954:Antigens, Surface / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D007111:Immunity, Cellular; D007376:Interleukin-2 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D015851:Interleukin-7 / Q000494:pharmacology*; D008198:Lymph Nodes / Q000166:cytology; D051379:Mice; D008815:Mice, Inbred Strains; D012513:Sarcoma, Experimental / Q000276:immunology / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D018800:Thy-1 Antigens
D000945:Antigens, Differentiation, T-Lymphocyte; D000954:Antigens, Surface; D007376:Interleukin-2; D015851:Interleukin-7; D018800:Thy-1 Antigens; D015847:Interleukin-4