Developing Novel Bispecific T-cell Engager Therapy by Concurrent Targeting GARP on Cancer Cells and Regulatory T cells 2258672

Abstract

Abstract Introduction While cancer immunotherapies have transformed treatment outcomes, most patients fail to respond primarily due to immune resistance mechanisms. Targeting tumor antigens along with suppressive factors may overcome such barriers. Glycoprotein A repetitions predominant (GARP) is a cell surface receptor that anchors latent transforming growth factor beta and contributes to immunosuppression, with its expression mostly to regulatory T cells (Tregs), cancer cells, and platelets. This study examines the therapeutic impact of engaging effector T cells to target GARP-expressing tumor cells along with Tregs, utilizing our unique anti-GARP antibody (PIIO-1) that targets tumors and Tregs but spares platelets. Methods We developed an anti-human GARP/CD3 bispecific T-cell Engager (BiTCE) with a tandem single-chain variable fragment construct. Human T cells armed with BiTCE were co-cultured with GARP+ tumor cells to assess cytotoxicity. In vivo efficacy and safety were evaluated using both immunocompromised and immunocompetent preclinical models that represent highly refractory diffuse large B-cell lymphoma, acute lymphoblastic leukemia, and glioblastoma. Importantly, we utilized systemic adeno-associated virus-mediated BiTCE delivery in vivo to overcome the pharmacokinetic challenges of short half-life of the typical BiTCE proteins without Fc. Results We demonstrate that elevated GARP expression in human tumors correlates with poor survival and higher relapse rates after first-line therapies. Our anti-GARP/CD3 BiTCE shows strong in vitro and in vivo efficacy against both GARP-expressing hematologic and solid tumor models without significant toxicity. Conclusion Our study provides a novel BiTCE therapeutic platform that enables us to achieve long-term tumor control and overcome tumor resistance by engaging CD3 on effector T cells to target GARP-expressing cancer and Tregs. The Anti-GARP/CD3 platform therefore holds the promise as a novel therapy of cancer immunotherapy worthy for clinical translation. Funding Source NIH R01 Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)