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.

Autor:	Kalaitsidou M; Department of Research, Instil Bio, Dallas, TX, United States., Moon OR; Department of Research, Instil Bio, Dallas, TX, United States., Sykorova M; Department of Research, Instil Bio, Dallas, TX, United States., Bao L; Department of Research, Instil Bio, Dallas, TX, United States., Qu Y; Department of Research, Instil Bio, Dallas, TX, United States., Sukumaran S; Department of Research, Instil Bio, Dallas, TX, United States., Valentine M; Department of Research, Instil Bio, Dallas, TX, United States., Zhou X; Department of Research, Instil Bio, Dallas, TX, United States., Pandey V; Ovarian Cancer Research Center, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States., Foos K; Ovarian Cancer Research Center, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States., Medvedev S; Ovarian Cancer Research Center, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States., Powell DJ Jr; Ovarian Cancer Research Center, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States., Udyavar A; Department of Research, Instil Bio, Dallas, TX, United States., Gschweng E; Department of Research, Instil Bio, Dallas, TX, United States., Rodriguez R; Department of Research, Instil Bio, Dallas, TX, United States., Dudley ME; Department of Research, Instil Bio, Dallas, TX, United States., Hawkins RE; Department of Research, Instil Bio, Dallas, TX, United States., Kueberuwa G; Department of Research, Instil Bio, Dallas, TX, United States., Bridgeman JS; Department of Research, Instil Bio, Dallas, TX, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2023 Nov 07; Vol. 14, pp. 1256491. Date of Electronic Publication: 2023 Nov 07 (Print Publication: 2023).
DOI:	10.3389/fimmu.2023.1256491
Abstrakt:	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 in vivo transplantable tumor model, CoStAR was shown to improve T cell survival after transfer, enhanced control of tumor growth, and improved host survival. CoStAR could be reliably engineered into TIL from multiple tumor indications and augmented TIL activity against autologous tumor targets both in vitro and in vivo . CoStAR thus represents a general approach to improving TIL therapy with synthetic costimulation. Competing Interests: 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. (Copyright © 2023 Kalaitsidou, Moon, Sykorova, Bao, Qu, Sukumaran, Valentine, Zhou, Pandey, Foos, Medvedev, Powell Jr, Udyavar, Gschweng, Rodriguez, Dudley, Hawkins, Kueberuwa and Bridgeman.)
Databáze:	MEDLINE
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