title: Tumor-specific CD4+ melanoma tumor-infiltrating lymphocytes.
abstract: Adoptive cell therapy using tumor-infiltrating lymphocytes (TIL) can mediate objective and durable tumor regressions in patients with metastatic melanoma. CD8+ tumor-reactive TIL are well studied in humans and animals, yet the function of tumor-infiltrating CD4+ T lymphocytes in patient treatments remains controversial. We recently demonstrated that CD4+ TILs are not necessary for objective responses in patients. Coinfusion with tumor-specific CD4 TIL may enhance or increase the durability of tumor regressions, but the number of patients with tumor-reactive CD4 TIL is unknown. We screened 44 CD8+-depleted TIL for in vitro reactivity against autologous tumor. Nine (20%) showed specific reactivity by interferon-γ release assay, of which 8 were specifically blocked by an anti-HLA-DR antibody. Flow-cytometric analysis of these reactive TIL confirmed a high CD4+ composition (median 89%). Highlighting the contribution of CD4+ TIL to tumor regression, a patient with widespread metastatic disease was administered TIL containing HLA class II-restricted tumor activity with high-dose interleukin-2 therapy after lymphodepletion that mediated regression of extensive metastatic disease in the liver and spleen. These results demonstrate that at least 20% of metastatic melanomas contain CD4+ lymphocytes with specific tumor recognition and suggest a possible role for CD4+ cells in the effectiveness of adoptive cell therapy.
authors.affiliation: Surgery Branch, National Cancer Institute, NIH, Bethesda, MD 20892-1201, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Friedman
authors.forename: Peter A
authors.initials: PA
authors.lastname: Prieto
authors.forename: Laura E
authors.initials: LE
authors.lastname: Devillier
authors.forename: Colin A
authors.initials: CA
authors.lastname: Gross
authors.forename: James C
authors.initials: JC
authors.lastname: Yang
authors.forename: John R
authors.initials: JR
authors.lastname: Wunderlich
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: Mark E
authors.initials: ME
authors.lastname: Dudley
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D049109:Cell Proliferation; D005260:Female; D006684:HLA-DR Antigens / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D007376:Interleukin-2 / Q000008:administration & dosage / Q000627:therapeutic use; D008113:Liver Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D008212:Lymphocyte Depletion; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000637:transplantation*; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D009928:Organ Specificity; D012878:Skin Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D013160:Splenic Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D014407:Tumor Cells, Cultured
chemical_list: D006684:HLA-DR Antigens; D007376:Interleukin-2; D007371:Interferon-gamma