Tumor-specific CD4+ melanoma tumor-infiltrating lymphocytes

Kevin M. Friedman, Peter A. Prieto, Laura E. Devillier, Colin A. Gross, James C. Yang, John R. Wunderlich, Steven A. Rosenberg, Mark E. Dudley

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)400-408
Number of pages9
JournalJournal of Immunotherapy
Volume35
Issue number5
DOIs
StatePublished - Jun 2012

Keywords

  • CD4+
  • HLA DR
  • Immunotherapy
  • T-helper cell (Th)
  • Tumor-infiltration lymphocytes (TIL)

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology
  • Cancer Research

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