4.6 Article

Robust Antitumor Responses Result from Local Chemotherapy and CTLA-4 Blockade

期刊

CANCER IMMUNOLOGY RESEARCH
卷 6, 期 2, 页码 189-200

出版社

AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-17-0356

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资金

  1. Ellen and Gary Davis Foundation
  2. Society of Surgical Oncology Clinical Investigator Award
  3. Cycle for Survival
  4. Cancer Center Support Grant from the National Institutes of Health [P30 CA008748]
  5. Ludwig Center at MSKCC
  6. Hilton-Ludwig Cancer Prevention Initiative Funding by the Conrad N. Hilton Foundation
  7. Ludwig Cancer Research
  8. Bristol-Myers Squibb
  9. NATIONAL CANCER INSTITUTE [P30CA008748] Funding Source: NIH RePORTER

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Clinical responses to immunotherapy have been associated with augmentation of preexisting immune responses, manifested by heightened inflammation in the tumor microenvironment. However, many tumors have a noninflamed microenvironment, and response rates to immunotherapy in melanoma have been <50%. We approached this problem by utilizing immunotherapy (CTLA-4 blockade) combined with chemotherapy to induce local inflammation. In murine models of melanoma and prostate cancer, the combination of chemotherapy and CTLA-4 blockade induced a shift in the cellular composition of the tumor microenvironment, with infiltrating CD8(+) and CD4(+) T cells increasing the CD8/Foxp3 T-cell ratio. These changes were associated with improved survival of the mice. To translate these findings into a clinical setting, 26 patients with advanced melanoma were treated locally by isolated limb infusion with the nitrogen mustard alkylating agent melphalan followed by systemic administration of CTLA-4 blocking antibody (ipilimumab) in a phase II trial. This combination of local chemotherapy with systemic checkpoint blockade inhibitor resulted in a response rate of 85% at 3 months (62% complete and23% partial response rate) and a 58% progression-free survival at 1 year. The clinical response was associated with increased T-cell infiltration, similar to that seen in the murine models. Together, our findings suggest that local chemotherapy combined with checkpoint blockade-based immunotherapy results in a durable response to cancer therapy. (C) 2018 AACR.

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