Signaling via a CD28/CD40 chimeric costimulatory antigen receptor (CoStAR™), targeting folate receptor alpha, enhances T cell activity and augments tumor reactivity of tumor infiltrating lymphocytes.

Transfer of autologous tumor infiltrating lymphocytes (TIL) to patients with refractory melanoma has shown clinical efficacy in a number of trials. However, extending the clinical benefit to patients with other cancers poses a challenge. Inefficient costimulation in the tumor microenvironment can lead to T cell anergy and exhaustion resulting in poor anti-tumor activity. Here, we describe a chimeric costimulatory antigen receptor (CoStAR) comprised of FRα-specific scFv linked to CD28 and CD40 intracellular signaling domains. CoStAR signaling alone does not activate T cells, while the combination of TCR and CoStAR signaling enhances T cell activity resulting in less differentiated T cells, and augmentation of T cell effector functions, including cytokine secretion and cytotoxicity. CoStAR activity resulted in superior T cell proliferation, even in the absence of exogenous IL-2. Using an

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Copyright © 2023 Kalaitsidou, Moon, Sykorova, Bao, Qu, Sukumaran, Valentine, Zhou, Pandey, Foos, Medvedev, Powell Jr, Udyavar, Gschweng, Rodriguez, Dudley, Hawkins, Kueberuwa and Bridgeman.

Déclaration de conflit d'intérêts

MK, OM, MD, RH, GK and JB are employees of Instil Bio. RH and JB are shareholders in Instil Bio. RH, JB, GK, OM, MK, RR and EG are named inventors on CoStAR patents. DP has received sponsored research funding and receives fees for advisory service from Instil Bio. DP also holds patents in the area of TIL enrichment and receives royalties for licensed TIL technologies from other commercial entities. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.