Novel combination immunotherapy with oncolytic adenovirus and immune checkpoint inhibitors for pancreatic ductal adenocarcinoma.

Abstract public domain (NIH RePORTER)

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and refractory malignancy, whose recent five- year survival rate remains only 13%. Lack of effective therapy is definitely one of the main reasons of this dismal prognosis. We want to develop an effective combination therapy with OAd and immunotherapy as a neoadjuvant therapy to improve the conversion rate for resectable cases and reduce relapse rates after surgery. PDAC is immunologically quiescent cancer showing strong resistance to immunotherapies (e.g. ICIs). One of the strong reasons of the resistance is the exhaustion of the T-cells in the tumors. The T-cells in PDAC tumors in patients and mouse models show a strong of exhaustion, but they are mostly intermediate exhausted T (TEXint) cells whose exhaustion is reversible. Therefore, the therapies reverting their exhaustion has high potential to make immunotherapies functional. For physical barrier due to strong desmoplasia, anatomical distraction can enhance infiltration of immune cell into PDAC tumor. Oncolytic adenoviruses (OAds) can change the immunosuppressive TME by induction of immunogenic cell death, and the tumor lysis destroys tumor anatomical structure. Cracking the defensive mechanisms of PDAC with OAd therefore has a high potential to lead to development of a breakthrough therapy for the treatment of PDAC patients. Our team has developed an OAd for the treatment of PDAC, applying an infectivity enhancement strategy based on genetic capsid modification and COX-2 promoter-based replication control for the treatment of PDAC (RGDCRAdCOX2F). This OAd shows a higher infectivity and selective replication in PDAC cells, and minimal replication in adjacent normal pancreas, and normal liver. In the context of the combination strategy, OAd RGDCRAdCOX2F that can induce viral oncolysis known as immunogenic cell death and anatomical tumor destruction will be optimal to be combined with the therapy with ICI. We hypothesize that RGDCRAdCOX2F will revert and/or suppress T-cell exhaustion and physical barriers in PDAC tumors, and realize an effective combination with ICIs for PDAC, particularly locally advanced PDACs. This project will apply immunocompetent, orthotopic in vivo models to investigate the potency of this combination pre-clinically. We will perform the experiments with orthotopic tumor for better representation and determine which ICI is the best to be combined with the OAd. In addition, we will assess the effect of combination therapy of the OAd and immune checkpoint inhibitor with live human tissue slices. To enable lager scale manufacturing for commercialization, We will generate a suspension cGMP producer cell line based on the cell line we used for cGMP production for the current monotherapy clinical trial. This phase I STTR will support the commercial development of RGDCRAdCOX2F as a combination therapy with ICIs. The results from this STTR combined with the data from the mono-therapy trial will determine which ICI should be combined with EUS-guided injection of RGDCRAdCOX2F to treat PDAC toward phase II STTR.

Public health relevance public domain (NIH RePORTER)

This phase I STTR will support the commercial development of a combination of infectivity-enhanced, COX2 promoter-controlled oncolytic adenovirus (RGDCRAdCOX2F) with ICIs for pancreatic ductal adenocarcinoma (PDAC). We will determine the effects of the combination therapy in orthotopic syngeneic PDAC mouse model and human PDAC live tissue slices, and suspension culture of the virus producer cells will be generated for commercial scale production. The results from this STTR combined with the data from the mono-therapy trial will determine which ICI should be combined with endoscopic ultrasound-guided injection of RGDCRAdCOX2F to treat PDAC toward phase II STTR.