Avid Bioservices Inc (CDMO)

[hutschi]

Robust antitumor responses result from local chemotherapy and CTLA-4 blockade.

Ariyan CE1, Brady MS2, Siegelbaum RH3, Hu J2, Bello DM2, Green J2, Fisher C4, Lefkowitz RA5, Panageas KS6, Pulitzer M7, Vignali M8, Emerson R8, Tipton C8, Robins H8, Merghoub T9, Yuan J10, Jungbluth A7, Blando J11, Sharma P11, Rudensky AY11, Wolchok JD9, Allison JP11.
Author information
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 non-inflamed 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 to 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 one 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.

https://www.ncbi.nlm.nih.gov/pubmed/29339377