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1060 EVOLVETM: a novel costimulatory T cell engager platform engineered for the treatment of immune suppressive tumors
  1. Jeremy Myers,
  2. Mohosin Sarkar,
  3. Abudukadier Abulizi,
  4. Eric Tam,
  5. Guixian Jin,
  6. Xingyue An,
  7. Evelyn Teran,
  8. Shu Shien Chin,
  9. Danielle Klaskin,
  10. Nana Adjoa Pels,
  11. Maria Hackett,
  12. Oksana Sergeeva,
  13. Hayden Karp,
  14. Julio Rodriguez,
  15. Sonali Dhindwal,
  16. Changqing Yuan,
  17. Zengzu Lai,
  18. Jennifer Zeiger,
  19. Amber Fearnley,
  20. Louis Matis and
  21. Jay Fine
  1. EvolvImmune Therapeutics, Branford, CT, USA


Background 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 (Blincyto®) and mosunetuzumab (Lunsumio®) 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 costimulation.

Methods 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.

Results We demonstrate that CD2 costimulation is superior to other forms of T cell costimulation in its ability to promote cytolytic costimulation, 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 costimulation without increasing cytokine release relative to matched CD3-bispecifics. We also demonstrate the modular nature of the EVOLVE platform across diverse tumor antigens including B7H4 (VTCN1), the B cell lymphoma antigen CD20 and a novel squamous tumor antigen ULBP2.

Conclusions 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.

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