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

Introduction/Rationale: 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.