TY - JOUR
T1 - Robust antitumor responses result from local chemotherapy and CTLA-4 Blockade
AU - Ariyan, Charlotte E.
AU - Brady, Mary Sue
AU - Siegelbaum, Robert H.
AU - Hu, Jian
AU - Bello, Danielle M.
AU - Rand, Jamie
AU - Fisher, Charles
AU - Lefkowitz, Robert A.
AU - Panageas, Kathleen S.
AU - Pulitzer, Melissa
AU - Vignali, Marissa
AU - Emerson, Ryan
AU - Tipton, Christopher
AU - Robins, Harlan
AU - Merghoub, Taha
AU - Yuan, Jianda
AU - Jungbluth, Achim
AU - Blando, Jorge
AU - Sharma, Padmanee
AU - Rudensky, Alexander Y.
AU - Wolchok, Jedd D.
AU - Allison, James P.
N1 - Funding Information:
C.E. Ariyan is a consultant/advisory board member of Bristol-Myers Squibb. M. Vignali is a project manager at Adaptive Biotechnologies. H. Robins is cofounder of and has ownership interest in Adaptive Biotechnologies. J.D. Wolchok reports receiving commercial research funding from and is a consultant/advisory board member for Bristol-Myers Squibb. No potential conflicts of interest were disclosed by the other authors.
PY - 2018/2
Y1 - 2018/2
N2 - 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.
AB - 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.
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U2 - 10.1158/2326-6066.CIR-17-0356
DO - 10.1158/2326-6066.CIR-17-0356
M3 - Article
C2 - 29339377
AN - SCOPUS:85041907904
SN - 2326-6066
VL - 6
SP - 189
EP - 200
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 2
ER -