Effective Combination Immunotherapy using Oncolytic Viruses to Deliver CAR Targets to Solid Tumors

Abstract

Chimeric antigen receptor (CAR)-engineered T cell therapy for solid tumors is limited by the lack of tumor-restricted and homogeneous expression of tumor antigens1,2. Therefore, we engineered an oncolytic virus to express a non-signaling, truncated CD19 (CD19t) protein for tumor-selective delivery, enabling targeting by CD19-specific CAR T cells. Infecting tumor cells with a chimeric oncolytic vaccinia virus coding for CD19t (OV19t) produced de novo CD19 surface-antigen expression prior to virus-mediated tumor lysis. Co-cultured CD19-CAR T cells secreted cytokines and elicited potent cytolytic activity against infected tumors. Using multiple mouse tumor models, intratumoral delivery of OV19t induced tumor expression of CD19t and improved tumor control following CD19-CAR T cell administration. CAR T cell–mediated tumor killing also promoted release of virus from dying tumor cells, which propogated tumor expression of CD19t. These data demonstrate a novel immunotherapy approach utilizing oncolytic viruses to promote de novo CAR T cell targeting of solid tumors.One Sentence SummaryWe describe a novel and effective combination immunotherapy utilizing oncolytic viruses to deliver de novo cell surface expression of CD19 antigen promoting CD19-CAR T cell anti-tumor responses against solid tumors.

Human Vaccines & Immunotherapeutics: news

“…The typhoid fever vaccine Vi-DT (International Vaccine Institute) was well tolerated and immunogenic in children aged 6-23 months in a Phase 2 trial. 6 Both one-and two-dose regimens induced comparable seroconversion rates. The vaccine consists of the Vi polysaccharide from Salmonella Typhi conjugated to diphtheria toxin.…”

CAR T Cell Therapy for Solid Tumors: Bright Future or Dark Reality?

“…Examples for oncolytics/CAR T cell therapy combinations include the administration of oncolytic viruses encoding BiTEs, cytokines, and/or checkpoint inhibitors, [271][272][273] or oncolytic viruses that encode CAR targets. 274,275 In addition, investigators have explored the use of T cells to directly deliver viruses into tumors. [276][277][278] Checkpoint blockade/ CAR T cell therapy combinations are actively being pursued, 279 including the aforementioned clinical studies combining mesothelin-CAR T cells with pembrolizumab for the treatment of mesothelioma.…”

Combination Immunotherapy Using Oncolytic Virus for the Treatment of Advanced Solid Tumors

“…The combination of HER2/neu (also known as ErbB-2) CAR-T cells and oncolytic adenovirus-expressing anti-PD-L1 and IL-2 remarkably improved survival compared with either form of therapy alone in head and neck squamous cell carcinoma xenograft mice [ 71 ]. Moreover, Park et al reported a novel therapeutic combination using both OVs and CAR-T therapy in their recent study [ 72 ]. They used an oncolytic chimeric orthopoxvirus carrying CD19t (OV19t) to generate CD19t at the tumor cell surface.…”

“…They used an oncolytic chimeric orthopoxvirus carrying CD19t (OV19t) to generate CD19t at the tumor cell surface. After the administration of the OV19t and CD19-CAR T cell combination, ~70% of tumor cells were positive for CD19t and showed increased CAR-T cell infiltration in human tumor (MDA-MB-468) xenograft mice [ 72 ]. These preclinical studies suggest the promising potential of this combination therapeutic strategy for cancer treatment.…”