Cancer cell-selective ectopic expression of CD20 as an antigen enables rituximab repurposing for solid tumor immunotherapy

Abstract

Despite the clinical success of cancer immunotherapies, their efficacy is often compromised by antigen-related problems, including heterogeneity, downregulation, loss, and off-tumor toxicity. To overcome these limitations that challenge the current immunotherapies dependent on native antigens, we here describe a new cancer immunotherapy strategy, which artificially and specifically expresses a clinical validated antigen on variant tumors and thus repurposes clinical antibody drugs to treat cancers not belonging to their indications. To authenticate the strategy, we delivered a CD20 gene under a control of NF-{kappa}B-specific promoter to tumors by adeno-associated virus and then treated them with a CD20 antibody, rituximab. We found that CD20 was selectively expressed in tumors and the followed rituximab treatment activated natural killer (NK) cell to kill cancer cells by antibody-dependent cellular cytotoxicity. We demonstrated that this strategy is effective not only in variant cultivated cancer cells, HCT116 spheroids, and patient-derived organoids of human colorectal cancer, but also in humanized mouse with HCT116 xenograft and immunocompetent mouse with CT26 transplant. The strategy showed high cancer cell specificity in both in vitro and in vivo treatments, leading to high security in animal treatments. This strategy thus creates a new modality of cancer immune-redirection therapy by repurposing the clinical validated both antigen and antibody.