한빛사논문
- 조회228
Pei Yun Teo 1+, Youngrock Jung 1+, David H. Quach 2+, Joanna Koh 3, Richard Weijie Ong 3, Angeline Goh 3, Alrina Tan 1, Chee Hoe Ng 1, Cheah Chen Seh 1, Kar Wai Tan 4, Ivan D Horak 5, Lionel Low 6
1Tessa Therapeutic (Singapore), Singapore, Singapore.
2Centre for Cell Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, TX., U.S.A
3Current address : Tikva Allocell Pte Ltd, Singapore
+These authors contributed equally to this work.
*Corresponding Author : Lionel Low
Abstract
Allogeneic chimeric antigen receptor (CAR)-expressing T cells offer many advantages over autologous therapies, but their benefits are curtailed by graft-versus-host disease (GvHD) and elimination by recipient immune cells. Moreover, just as with autologous therapies, allogeneic CAR T cells are susceptible to activation-induced cell death (AICD) caused by chronic antigen exposure (CAE). Granzyme B (GzmB) and Fas/FasL-initiated, caspase-mediated apoptosis are key mechanisms of T-cell death caused by T/NK cell–mediated allorejection or CAE. We explored a protective strategy of engineering CAR T cells to overexpress variants of the GzmB-specific serine protease inhibitor, SerpinB9 (SB9), to improve allogeneic T-cell persistence and antitumor efficacy. We showed that the overexpression of an SB9 variant with broadened caspase specificity, SB9(CAS), not only significantly reduced rejection of allogeneic CAR T cells, but also increased their resistance to AICD and enabled them to thrive better under CAE, thus improving allogeneic T-cell persistence and antitumor activity in vitro and in vivo. In addition, while SB9(CAS)-overexpression improved the efficacy of allogeneic CAR T-cell therapy by conferring protection to cell death, we did not observe any autonomous growth and the engineered CAR T cells were still susceptible to an inducible suicide switch. Hence, SB9(CAS)-overexpression is a promising strategy that can strengthen current development of cell therapies, broadening their applications to address unmet medical needs.
논문정보
- Research article
- 2024년 06월 (BRIC 등록일 2024-06-10)
- 국외 연구진
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