Renal cell cancer is highly resistant to conventional chemotherapies. Adoptive transfer of tumor-infiltrating lymphocytes (TIL) with interleukin-2 (IL-2) produces objective anti-tumor responses in approximately 25% of patients with metastatic renal cell carcinoma. To date, the TIL used in therapy have displayed significant variation in their subset composition and in their functional activities. Adoptive transfers of CD4+ lymphocytes can modulate the immune response and yield anti-tumor responses in vivo. IFN-gamma induces expression of Ia antigens by tumor and other cells, and promotes the anti-tumor effects of IL-2 in vivo. We will examine the effects of adoptive therapy with CD4+ TIL in combination with recombinant human IL-2 (3xlO-6 U/M-2/24hr) and IFN-gamma (0.1 mg/M-2/day) in the treatment of patients with metastatic renal cell carcinoma. Approximately 1011 highly purified CD+ TIL will be generated for therapy by stimulating tumor biopsies with a bispecific murine antibody (anti-CD3, CD8) that simultaneously selects and expands CD4+ lymphocytes from mixed populations of TIL. CD4+ and CD8+ TIL will be characterized for their proliferative and cytolytic activities against autologous and allogeneic tumors, and for their repertoire of lymphokine secretion. The inflammatory response to tumors will be analyzed in situ before and after therapy. Changes in lymphokine production by TIL and PBL in vivo will be evaluated by mRNA amplification phenotyping (MAPPing). The frequency of tumor-reactive TIL will be determined by limiting dilution analysis, before and after therapy.
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