Abstract B44: EVOLVE: A novel costimulatory T cell engager platform engineered for the treatment of solid tumors


 CD3-bispecifics are antibody-based therapies that can simultaneously bind to a tumor cell surface antigen and T cells to establish a synapse between the tumor and T cell and activate T cell to induce specific killing of the tumor cell. CD3-bispecifics have demonstrated clinical success in B cell acute lymphoblastic leukemia and follicular lymphoma with approvals of that blinatumomab and mosunetuzumab that target B cell lineage antigens CD19 and CD20, respectively. However, clinical progress in deploying CD3-bispecifics for positive patient outcomes in solid tumors has been slow, due to tumor microenvironmental factors such as induction of T cell exhaustion, as well as the potential of CD3-bispecifics to mediate T cell anergy and dysfunction in the absence of adequate co-stimulation. Here we describe the development and preclinical validation of the EVOLVE platform, a tumor-targeted biologic that induces the formation of a synthetic synapse that simultaneously activates the T cell receptor complex and the CD2 receptor to optimize CD8 T cell effector phenotype and improve tumor cell killing ex vivo and in vivo, compared to matched CD3-bispecifics. We demonstrate that CD2 co-stimulation is superior to other forms of T cell co-stimulation in its ability to promote cytolytic co-stimulation, T cell cytokine production and T cell expansion. Furthermore, CD2 receptor expression is markedly elevated in tumor infiltrating lymphocytes across a broad set of tumor types, relative to the CD28 and 4-1BB costimulatory receptors. EVOLVE-mediated T cell activation is conditionally dependent on tumor antigen binding and can be tuned to promote optimal co-stimulation without increasing cytokine release relative to matched CD3-bispecifics. We also demonstrate the modular nature of the EVOLVE platform across diverse solid tumor antigens including B7H4 (VTCN1), and a novel squamous tumor antigen ULBP2. Our data highlight the broad applications of the EVOLVE platform to improve CD8 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: Mandy Shu Shien Chin, Mohosin Sarkar, Eric Tam, Abudukadier Abulizi, Guixian Jin, Xingyue An, Evelyn Teran, Danielle M Klaskin, Nana Adjoa Pels, Maria Hackett, Oksana A Sergeeva, Hayden Karp, Julio Rodriguez, Sonali Dhindwal, Changqing Yuan, Zengzu Lai, Jennifer Zeiger, Amber Fearnley, Louis Matis, Jay Fine, Jeremy S Myers. EVOLVE: A novel costimulatory T cell engager platform engineered for the treatment of solid tumors [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B44.