Injected intratumorally, adenoviruses expressing IFNβ and a membrane-bound CD40L activated tumor cDCs and induced lymph node migration and tumor antigen trafficking. IFNβ and CD40L had distinct and complementary effects in increasing human monocyte-derived DC activation, and CD8+ T cell priming, tumor infiltration, and antitumor efficacy in mouse tumor models. The adenoviral combo treatment synergized with ICB to restrain growth of injected and contralateral tumors, extending mouse survival. Formatted as an oncolytic virus, this therapy increased T cell clonotype diversity and tumor infiltration in a phase 1A clinical trial.
Contributed by Alex Najibi
ABSTRACT: Oncolytic viral therapies induce direct killing of tumor cells and activation of conventional dendritic cells (cDCs); however, cDC activation has not been optimized with current therapies. We evaluated adenoviral delivery of engineered membrane-stable CD40L (MEM40) and IFNβ to locally activate cDCs in mouse tumor models. Combined tumor MEM40 and IFNβ expression induced the highest cDC activation coupled with increased lymph node migration, increased systemic antitumor CD8+ T-cell responses, and regression of established tumors in a cDC1-dependent manner. MEM40+IFNβ combined with checkpoint inhibitors led to effective control of distant tumors and lung metastases. An oncolytic adenovirus (MEM-288) expressing MEM40+IFNβ in phase 1 clinical testing induced cancer cell loss concomitant with enhanced T-cell infiltration and increased systemic presence of tumor T-cell clonotypes in NSCLC patients. This approach to simultaneously target two major DC-activating pathways has potential to significantly impact the solid tumor immunotherapy landscape.
Author Info: (1) Moffitt Cancer Center and Research Institute, Tampa, FL, United States. (2) Moffitt Cancer Center, Tampa, FL, United States. (3) Moffitt Cancer Center, Tampa, United States. (4
Author Info: (1) Moffitt Cancer Center and Research Institute, Tampa, FL, United States. (2) Moffitt Cancer Center, Tampa, FL, United States. (3) Moffitt Cancer Center, Tampa, United States. (4) Moffitt Cancer Center, Tampa, United States. (5) Moffitt Cancer Center, United States. (6) Moffitt Cancer Center, Tampa, FL, United States. (7) Moffitt Cancer Center, Tampa, FL, United States. (8) Moffitt Cancer Center, Tampa, FL, United States. (9) H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States. (10) Duke University School of Medicine, Durham, NC, United States. (11) Duke Medical Center, Durham, NC, United States. (12) H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States. (13) Memgen, Inc., Houston, TX, United States. (14) H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States.
