Crupi Mathieu J. F. , Taha Zaid , Janssen Thijs J. A. , Petryk Julia , Boulton Stephen , Alluqmani Nouf , Jirovec Anna , Kassas Omar , Khan Sarwat T. , Vallati Sydney , Lee Emily , Huang Ben Zhen , Huh Michael , Pikor Larissa , He Xiaohong , Marius Ricardo , Austin Bradley , Duong Jessie , Pelin Adrian , Neault Serge , Azad Taha , Breitbach Caroline J. , Stojdl David F. , Burgess Michael F. , McComb Scott , Auer Rebecca , Diallo Jean-Simon , Ilkow Carolina S. , Bell John Cameron , Oncolytic virus driven combination immunotherapy shows promise in colorectal cancer published in Frontiers.



As one of the most common and fatal types of cancer, colorectal cancer represents a clinical challenge and opportunity for novel therapies. While immunotherapy has been broadly successfully in other tumor types including melanoma and non-small cell lung cancer, clinical utility in colorectal cancer is currently limited to those tumors displaying microsatellite instability.  


In this study a team of investigators led by John Cameron Bell describe a novel combination of T-cell based immunotherapy and oncolytic viruses. T-cell engagers (TCEs) are immunomodulatory molecules that bind to a tumor associated antigen and CD3 on T cells, promoting recruitment to the tumor. TCEs have been approved for treatment of hematologic malignancies, but application to solid tumors has remained a challenge largely due to the inability of TCEs to penetrate solid tumors. TCE delivery via oncolytic virus has been proposed as a way to overcome this limitation.  


This group began their research by generating and validating TCEs to target colorectal cancer cells. They chose to target CEA (an antigen found on colorectal cancer cells) and validated TCEs with both mouse and human CD3. They tested their TCEs in a cell culture model and found that activation of CD4 and CD8-postivie T cells occurred in in vitro models. However, the TCEs did not display the same efficacy in vivo due to their short half-life and inability to penetrate the tumor microenvironment.  


In order to create an oncolytic virus to deliver their TCEs, the researchers tested several viruses and identified vaccina virus as the best candidate for infection of colorectal tumors. They created a Bispecific Engager Virus (BEVir) armed with TCEs targeting CEA. They found that infected cells secreted TCE and that the TCE was specific. In tissue culture models, they observed cell death upon infection with the BEVir and found that cellular production of TCE resulted in a greater killing effect than TCE deliver alone. The then turned to mouse models for further experiments and saw tumor regression in both syngeneic and xenograft colorectal cancer models.  


Having established that their viral method for TCE delivery had antitumor activity, the scientists wanted to test immune checkpoint inhibition as a way to maintain the efficacy of TCEs in models of aggressive peritoneal metastasis. Utilizing Bio X Cell’s Ipilimumab biosimilar antibody (SIM0004) for in vivo CTLA-4 neutralization in humanized mice, they found that immune checkpoint inhibition increased survival in this model of aggressive colorectal cancer. Encoding anti CTLA4 into the vaccinia virus also allowed for combination viro-immunotherapy and significantly prolonged survival.  


In summary, these experiments describe a novel strategy for attacking colorectal cancer cells utilizing viruses encoding TCEs and immunotherapy to create sustained tumor killing in aggressive disease models. This combination holds promise for development of novel treatments and expansion of the use of immunotherapy for colorectal cancer.