Induction of cytotoxicity of human tumor-infiltrating lymphocytes against autologous tumor cells and its application for cancer therapy

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1) Cancer patients were treated with the adoptive immunotherapy with lymphokine-activated killer (LAK) cells which were induced by culture of autologous peripheral blood lymphocytes (PBL) with interleukin-2(IL-2). Local administration by intraarterial or intracavital infusions of LAK cells produced a superior therapeutic efficacy to systemic administration by intravenous infusions.2)A half of tumor-infiltrating cells into human solid cancers consisted of T lymphocytes and the proportion of CD8^+T lymphocytes were greater than that of PBL.Tumor-infiltrating lymphocytes (TIL) contained gammadelta T cells and the majority of those cells in colorectal cancers were CD8^+ gammadelta T cells whose lineage was different from that of PBL.Hepatocellular carcinoma contained a greater number of gammadelta TIL than other human solid cancers.3)Culture of TIL with IL-2 alone was inadequate for their in vitro expansion, and we found that TIL effectively expanded in culture by addition of 20% conditioned medium derived from LAK cell induction.4)Cytotoxicity against tumor cells was notdetected in freshly isolated TIL.Cytotoxicity of TIL gradually increased in culture, reached its maximum at 2 to 3 weeks, and disappeared at 4 to 7 weeks. Phytohemagglutinin (PHA) was found to be capable of partial restoration of the diminished cytotoxicity of cultured TIL.5) TIL of advanced gastric cancer were activated in vivo by preoperative intratumoral injection with a biological response modifier, OK-432, and survival of patients after curative sugery was compared with control patients. Although there was no difference in survival of patients with scanty TIL,the activation of TIL improved 3-year survival in patients with TIL of a medium or over degree.