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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 + 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.

Supplementary Figure 1. Gemcitabine and CTLA-4 blockade synergize to create an inflammatory microenvironment and anti-tumor response. Mice with palpable tumors were treated with low dose gemcitabine followed by systemic CTLA-4 blockade. Survival was improved (A) and tumors with combination treatment had a significant influx in CD4 and CD8 Tcells (B). Elispot (C) demonstrated improved enhanced IFNγ in response to SPAS-1 peptide (SNC9H8). Supplemental Figure S2. Lack of significant change of TIM3 or LAG3 over time in peripheral blood mononuclear cells (PBMC) over time. Supplementary Table S1. Toxicities in the limb according to Wieberdink criteria Supplemental Table 2. Nanostring fold change results of all genes

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