CD40 is a cell-surface member of the TNF receptor superfamily that upon activation can license dendritic cells (DC) to promote antitumor T-cell activation and re-educate macrophages to destroy tumor stroma. Mechanistically, the combination of chemotherapy followed by CD40 mAb functions as an “in situ” vaccine; in addition, destruction of stroma by CD40-activated macrophages may enhance chemotherapy delivery. In a recent study sponsored by the Parker Institute of Cancer Immunotherapy of gemcitabine and nab-paclitaxel chemotherapy plus CD40 mAb APX005M, with or without PD-1 nivolumab mAb, we found the objective response rate among 30 patients with untreated, metastatic pancreatic cancer was more than 50% in the DLT-evaluable population. 13 patients experienced an AE leading to discontinuation, and 10 patients experienced a treatment-related serious AE. Two DLTs were observed, grade 3 and 4 febrile neutropenia, respectively. A three-arm randomized study of gemcitabine, nab-paclitaxel with APX005M, or with nivolumab, or with both APX005M and nivolumab has completed enrollment. Evidence to date suggests that CD40 activation is a critical and nonredundant mechanism to convert “cold” tumors to “hot” (with prominent tumor infiltration of T cells), sensitizing them to checkpoint inhibition.

Citation Format: Robert H. Vonderheide. CD40 immunotherapy for pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I12.