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Cancer Immunol Res. 2018 Feb;6(2):189-200. doi: 10.1158/2326-6066.CIR-17-0356. Epub 2018 Jan 16.

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

Author information

1
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. ariyanc@mskcc.org.
2
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
3
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
4
Department of Anesthesia, Memorial Sloan Kettering Cancer Center, New York, New York.
5
Department of Statistics, Memorial Sloan Kettering Cancer Center, New York, New York.
6
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
7
Adaptive Biotechnology, Seattle, Washington.
8
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
9
Department of Immunology, MD Anderson Cancer Center, Houston, Texas.
10
Department of Immunology, Memorial Sloan Kettering Cancer Center, New York, New York.
#
Contributed equally

Abstract

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 and 23% 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. Cancer Immunol Res; 6(2); 189-200. ©2018 AACR.

PMID:
29339377
DOI:
10.1158/2326-6066.CIR-17-0356
[Indexed for MEDLINE]
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