RT Journal Article
SR Electronic
T1 Robust Antitumor Responses Result from Local Chemotherapy and CTLA-4 Blockade
JF Cancer Immunology Research
JO Cancer Immunol Res
FD American Association for Cancer Research
SP 189
OP 200
DO 10.1158/2326-6066.CIR-17-0356
VO 6
IS 2
A1 Ariyan, Charlotte E.
A1 Brady, Mary Sue
A1 Siegelbaum, Robert H.
A1 Hu, Jian
A1 Bello, Danielle M.
A1 Rand, Jamie
A1 Fisher, Charles
A1 Lefkowitz, Robert A.
A1 Panageas, Kathleen S.
A1 Pulitzer, Melissa
A1 Vignali, Marissa
A1 Emerson, Ryan
A1 Tipton, Christopher
A1 Robins, Harlan
A1 Merghoub, Taha
A1 Yuan, Jianda
A1 Jungbluth, Achim
A1 Blando, Jorge
A1 Sharma, Padmanee
A1 Rudensky, Alexander Y.
A1 Wolchok, Jedd D.
A1 Allison, James P.
YR 2018
UL http://cancerimmunolres.aacrjournals.org/content/6/2/189.abstract
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 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.