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

Vollständiger Abstract

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Abstract Background Despite the clinical success of cancer immunotherapies, their efficacy is often compromised by antigen‐related problems, including downregulation, loss, and off‐tumour toxicity. Methods To overcome these limitations that challenge the current immunotherapies dependent on native antigens, we here describe a new cancer immunotherapy strategy that artificially and specifically expresses a clinically validated antigen on variant tumours and thus repurposes clinical antibody drugs to treat cancers not belonging to their indications. To authenticate the strategy, we delivered a CD20 gene under the control of an NF‐κB‐specific promoter to tumours by adeno‐associated virus and then treated them with a CD20 antibody, rituximab. Results We found that CD20 was selectively expressed in tumours, and subsequent rituximab treatment engaged multiple antibody‐dependent effector mechanisms, including NK‐cell‐mediated ADCC and macrophage‐mediated ADCP. 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 a humanized mouse with an HCT116 xenograft and immunocompetent mouse with an MC38 transplant. The strategy showed high cancer cell specificity in both in vitro and in vivo models, resulting in high therapeutic efficacy. Conclusion This strategy thus creates a new modality of cancer immune‐redirection therapy by repurposing both the clinically validated antigen and antibody. Key points TRAP enables tumour‐selective ectopic expression of the clinically validated antigen CD20, overcoming antigen limitations in solid tumour immunotherapy. TRAP repurposes anti‐CD20 antibodies to engage diverse immune effector mechanisms, including ADCC, ADCP, and CDC. TRAP demonstrates antitumour efficacy across cellular, 3D tumour spheroid, patient‐derived organoid, and in vivo solid tumour models.