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Bispecific antibodies which bind a tumor antigen and the CD3 heterodimer of the T cell receptor to form a synthetic immunological synapse represent a class of T cell engagers that has been clinically validated with the approvals of blinatumomab (Blinctyo®) and mosunetuzumab (Lunsumio®), targeting CD19 and CD20 respectively, for the treatment of B cell acute lymphoblastic leukemia and follicular lymphoma. Despite being a potent class of therapeutics, not all patients respond to therapy. Recent studies into state of blinatumomab-treated T cells highlight exhaustion and the lack of co-stimulation as potential factors in resistance. In solid tumors, the immunosuppressive tumor microenvironment is also a major factor while cytokine release is a safety consideration for all bispecifics that bind CD3 with strong affinity. To address the challenges of CD3 bispecifics, we have developed the EVOLVE™ platform, a trispecific antibody that consists of tumor targeting and attenuated CD3 binding affinity coupled with a CD2 agonist. We show that CD2 costimulation is superior to other pathways in its ability to sustain T cell activation and expansion and cytokine production over repeated cycles of stimulation. By integrating a CD2 agonist with an attenuated CD3 affinity bispecific, we can restore cytolytic potential without concomitant increase in cytokine release as compared to a strong CD3 affinity bispecific. The EVOLVE platform is also capable of inducing tumor cell killing by in vitro exhausted T cells whereas the bispecific did not. In terms of safety, the EVOLVE platform does not induce peripheral T cell activation and cytokine release in PBMCs in the absence of target as compared to CD3 and CD28 agonist antibodies. The superiority of the EVOLVE platform compared to a bispecific was also demonstrated in vivo where we observed 8/8 complete responses in EVOLVE-treated animals whereas the strong CD3 affinity bispecific showed no difference compared to isotype control using a CORL105 lung cancer xenograft model. We believe these experiments recapitulate the continual clinical challenges of using strong CD3 affinity bispecifics while demonstrating the advantages of the EVOLVE platform. Finally, we demonstrate the modular nature of the EVOLVE platform across diverse tumor antigens including B7H4, PSMA, CD20, and a novel squamous tumor antigen ULBP2. Together our data highlight the broad applications of the EVOLVE platform to improve T cell-mediated anti-tumor immunity and suggest its potential as an emerging, first-in-category immunotherapeutic strategy to address unmet medical needs in oncology. Citation Format: Mohosin Sarkar, Eric M. Tam, Guixian Jin, Shu Shien Chin, Abudukadier Abulizi, Oksana A. Sergeeva, Zengzu Lai, Evelyn Teran, Hayden Karp, Danielle Klaskin, Nana Adjoa Pels, Xingyue An, Jennifer Ziegler, Changqing Yuan, Maria Hackettt, Sonali Dhindwal, Amber Fearnley, Julio Rodriguez, Louis Matis, Jay S. Fine, Jeremy S. Myers. EVOLVETM: A novel T cell engager platform with integrated CD2 costimulation engineered for the treatment of immune suppressive tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2971.