The incubation of murine or human lymphocytes in high concentrations of purified Interleukin 2 (IL 2) induces the generation of cytolytic effector cells, termed lymphokine activated killer (LAK) cells. LAK cells are markedly cytotoxic in vitro to a wide spectrum of tumor cell targets, including fresh autologous human tumor; and, the adoptive transfer of LAK cells has been shown to be effective therapy for a variety of murine tumors. Similarly, the administration of high-dose IL 2 in vivo can induce LAK activity from host precursor cells and mediate an anti-tumor effect. Phase I clinical trials for the use of IL 2 and/or LAK cells in humans for cancer therapy have been initiated by several research groups including our own. The purpose of the proposed studies is to further evaluate in murine models the immunobiology, therapeutic efficacy and toxicity of LAK cells and of high-dose IL 2 in order to elucidate the principles necessary for the effective use of such therapy in man.
The specific aims of the proposed research are: (1) To determine the phenotype of LAK effector cells potentially operative in tumor therapy; (2) To determine whether LAK effector cells can be expanded in number by long-term culture in vitro and thereby rendered more effective in therapy; (3) To determine the kinetics of survival and the distribution of donor LAK cells in vivo; (4) To determine the effect of exogenous IL 2 on the survival, distribution and function of donor LAK cells in vivo; (5) To determine whether host immunosuppression can increase the transferability and function of donor LAK cells; (6) To determine the kinetics of LAK cell generation in vivo induced by administration of high-dose IL 2; (7) To compare the efficacy and toxicity of high-dose IL 2 in vivo versus adoptively transferred LAK cells plus lower-dose IL 2; and, (8) To determine the effect of cytotoxic chemotherapy or radiation therapy on the subsequent ability to generate LAK cells in vitro or in vivo.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Experimental Immunology Study Section (EI)
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University of Washington
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Chen, W; Cheever, M A (1994) Donor T cells can be induced to grow and survive long term in vivo without previous host immunosuppression. J Immunol 152:4767-74
Peace, D J; Smith, J W; Chen, W et al. (1994) Lysis of ras oncogene-transformed cells by specific cytotoxic T lymphocytes elicited by primary in vitro immunization with mutated ras peptide. J Exp Med 179:473-9
Peace, D J; Smith, J W; Disis, M L et al. (1993) Induction of T cells specific for the mutated segment of oncogenic P21ras protein by immunization in vivo with the oncogenic protein. J Immunother Emphasis Tumor Immunol 14:110-4
Crossland, K D; Lee, V K; Chen, W et al. (1991) T cells from tumor-immune mice nonspecifically expanded in vitro with anti-CD3 plus IL-2 retain specific function in vitro and can eradicate disseminated leukemia in vivo. J Immunol 146:4414-20
Peace, D J; Chen, W; Nelson, H et al. (1991) T cell recognition of transforming proteins encoded by mutated ras proto-oncogenes. J Immunol 146:2059-65
Schultz, K R; Klarnet, J P; Peace, D J et al. (1990) Monoclonal antibody therapy of murine lymphoma: enhanced efficacy by concurrent administration of interleukin 2 or lymphokine-activated killer cells. Cancer Res 50:5421-5
Chen, W; Reese, V A; Cheever, M A (1990) Adoptively transferred antigen-specific T cells can be grown and maintained in large numbers in vivo for extended periods of time by intermittent restimulation with specific antigen plus IL-2. J Immunol 144:3659-66
Peace, D J; Cheever, M A (1989) Toxicity and therapeutic efficacy of high-dose interleukin 2. In vivo infusion of antibody to NK-1.1 attenuates toxicity without compromising efficacy against murine leukemia. J Exp Med 169:161-73
Peace, D J; Kern, D E; Schultz, K R et al. (1988) IL-4-induced lymphokine-activated killer cells. Lytic activity is mediated by phenotypically distinct natural killer-like and T cell-like large granular lymphocytes. J Immunol 140:3679-85