title: Patterns of cytokine release of unselected and CD8+ selected renal cell carcinoma tumor-infiltrating lymphocytes (TIL). Evidence for enhanced specific killing of tumor necrosis factor-secreting/IL-6 nonsecreting TIL in vitro and correlation with complete response in vivo.
abstract: Murine systems have demonstrated improved anti-tumor efficacy when tumor-infiltrating lymphocytes (TIL) are combined with interleukin-2 (IL-2). One goal of human adoptive immunotherapy is to identify and expand TIL with specific activity against autologous tumor. In this study we attempted to isolate and characterize such cells by phenotype and cytokine expression pattern. Fourteen unselected (bulk) TIL and 5 CD8+ selected cultures were established from primary renal cell carcinoma. All cultures were grown in the presence of IL-2; triplicate cultures of each TIL culture were grown in IL-2 alone or were intermittently cocultured with irradiated allogeneic or autologous tumor. The in vitro cytotoxicity, phenotype, and cytokine expression pattern as defined by the secretion of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma, granulocyte-macrophage colony-stimulating factor, IL-4, IL-6, and IL-12 were evaluated for each culture. While there was significant heterogeneity among the cultures under differing culture conditions as characterized by cytotoxicity, phenotype, and cytokine secretion pattern, we identified 8 TIL cultures which demonstrated specific enhanced lysis of only autologous tumor upon exposure to irradiated autologous tumor in vitro. These cultures demonstrate a decreased proportion of cells expressing the phenotype CD11b+. More importantly, these cultures were defined by the cytokine secretion phenotype TNF(+)/IL-6(-) upon exposure to irradiated autologous tumor. When utilized in vivo in adoptive immunotherapy of metastatic renal cell carcinoma together with IL-2, complete resolution of all metastatic tumor has only been achieved in patients who received TIL with the cytokine profile TNF(+)/IL-6(-). These findings suggest that tumor-specific renal TIL with enhanced tumor-specific cytotoxicity can be generated in vitro and can be characterized by a specific pattern of cytokine secretion. In addition, patients who receive TIL characterized by the cytokine profile TNF(+)/IL-6(-) may have an improved outcome when receiving immunotherapy.
authors.affiliation: Department of Surgery, UCLA School of Medicine 90024-1738.
authors.forename: G G
authors.initials: GG
authors.lastname: Steger
authors.forename: W C
authors.initials: WC
authors.lastname: Pierce
authors.forename: R
authors.initials: R
authors.lastname: Figlin
authors.forename: J
authors.initials: J
authors.lastname: Czernin
authors.forename: R
authors.initials: R
authors.lastname: Kaboo
authors.forename: J B
authors.initials: JB
authors.lastname: DeKernion
authors.forename: T
authors.initials: T
authors.lastname: Okarma
authors.forename: A
authors.initials: A
authors.lastname: Belldegrun
mesh_terms: D016827:CD8 Antigens / Q000276:immunology*; D002292:Carcinoma, Renal Cell / Q000276:immunology* / Q000628:therapy*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic; D006801:Humans; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive; D007376:Interleukin-2 / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D007680:Kidney Neoplasms / Q000276:immunology* / Q000628:therapy*; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D016177:Macrophage-1 Antigen / Q000502:physiology; D017063:Outcome Assessment, Health Care; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016827:CD8 Antigens; D016207:Cytokines; D007376:Interleukin-2; D015850:Interleukin-6; D016177:Macrophage-1 Antigen; D014409:Tumor Necrosis Factor-alpha