Robust Antitumor Responses Result from Local Chemotherapy and CTLA-4 Blockade. Academic Article uri icon

Overview

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.

publication date

  • January 16, 2018

Research

keywords

  • Antineoplastic Combined Chemotherapy Protocols
  • CTLA-4 Antigen
  • Melanoma

Identity

PubMed Central ID

  • PMC6857638

Scopus Document Identifier

  • 85041907904

Digital Object Identifier (DOI)

  • 10.1158/2326-6066.CIR-17-0356

PubMed ID

  • 29339377

Additional Document Info

volume

  • 6

issue

  • 2