Systemic administration of recombinant human interleukin 2 (IL 2)-expanded tumor infiltrating lymphocytes (TIL) obtained from freshly resected surgical specimens is an experimental approach to adoptive immunotherapy of cancer. When adoptively transferred in conjunction with IL-2, TIL are capable of mediating significant cancer regressions in tumor bearing patients. The goal of this work is to find methods to increase potency of TIL immunotherapy and abbrogate dose-dependent toxicity associated with the administration of IL-2. Malignant melanoma and renal cell cancer (ROC) are tumors particularly responsive to immunotherapy. TIL extracted from patients with melanoma can often exhibit long term specific lysis of autologous but not allogeneic tumors. TIL isolated from ROC, however, demonstrate a nonspecific (polyclonal) killing activity, which they tend to lose after about 3 weeks in culture. In animal models, therapy with tumor specific cells requires substantially fewer cells as well as less IL-2. Our recent isolation of a TIL clones with highly specific reactivity to the autologous ROC suggests that specific host immune response against ROC does, in fact, exist. The purpose of the proposed studies is therefore to determine, in patients with ROC, the optimal conditions under which potent tumor-specific effector cells can be selectively grown our from a heterogeneous population of TIL, to characterize lymphoid lines and clones with absolute lytic specificity vs. cells with non-specific lytic activity, and to determine the cellular and molecular mechanisms leaking to maximal activation in vitro of lymphoid cells that have been specifically sensitized the autologous ROC. The studies seek to: characterize tumor- reactive TIL lines and their derived clones, that have been co-culture with autologous tumor cells and/or grown in the presence of low (rather than high) concentrations of IL-2; elucidate the effector functions of TIL following vitro incubations with biologic response modifiers (such as IL-4 and IL-6); study gene expression and lymphokine production by parental and clonal populations of specifically sensitized TIL; subclassify renal TIL clones based on their lymphokine expression/productions vs. their in vitro functional activity. Understanding of the requirements for selective activation of specific vs. nonspecific TIL subsets, and of the role of each subset in the induction of potent effector cells is crucial for future development of new immunological approaches to the treatment of cancer. Based on the above information the project will explore the feasibility of systemically administrating tumor-specific TIL to patients with advanced ROC. The investigator will attempt to determine in these patients whether any of the mRNAs coding for various lymphokines produced by TIL can serve as a marker for clinical response following TIL immunotherapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Experimental Therapeutics Subcommittee 1 (ET)
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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