Robust antitumor responses result from local chemotherapy and CTLA-4 Blockade

Charlotte E. Ariyan, Mary Sue Brady, Robert H. Siegelbaum, Jian Hu, Danielle M. Bello, Jamie Rand, Charles Fisher, Robert A. Lefkowitz, Kathleen S. Panageas, Melissa Pulitzer, Marissa Vignali, Ryan Emerson, Christopher Tipton, Harlan Robins, Taha Merghoub, Jianda Yuan, Achim Jungbluth, Jorge Blando, Padmanee Sharma, Alexander Y. RudenskyJedd D. Wolchok, James P. Allison

Research output: Contribution to journalArticle

38 Scopus citations

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 and23%partial response rate) and a58% 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.

Original languageEnglish (US)
Pages (from-to)189-200
Number of pages12
JournalCancer Immunology Research
Volume6
Issue number2
DOIs
StatePublished - Feb 2018

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ASJC Scopus subject areas

  • Immunology
  • Cancer Research

Cite this

Ariyan, C. E., Brady, M. S., Siegelbaum, R. H., Hu, J., Bello, D. M., Rand, J., Fisher, C., Lefkowitz, R. A., Panageas, K. S., Pulitzer, M., Vignali, M., Emerson, R., Tipton, C., Robins, H., Merghoub, T., Yuan, J., Jungbluth, A., Blando, J., Sharma, P., ... Allison, J. P. (2018). Robust antitumor responses result from local chemotherapy and CTLA-4 Blockade. Cancer Immunology Research, 6(2), 189-200. https://doi.org/10.1158/2326-6066.CIR-17-0356