PD-1 and TIGIT downregulation distinctly affect the effector and early memory phenotypes of CD19-targeting CAR T cells
Young-Ho Lee, Hyeong Ji Lee, Hyung Cheol Kim, Yujean Lee, Su Kyung Nam, Cedric Hupperetz, Jennifer S Y Ma, Xinxin Wang, Oded Singer, Won Seog Kim, Seok Jin Kim, Youngil Koh, Inkyung Jung, Chan Hyuk Kim, Young-Ho Lee, Hyeong Ji Lee, Hyung Cheol Kim, Yujean Lee, Su Kyung Nam, Cedric Hupperetz, Jennifer S Y Ma, Xinxin Wang, Oded Singer, Won Seog Kim, Seok Jin Kim, Youngil Koh, Inkyung Jung, Chan Hyuk Kim
Abstract
CD19-targeting chimeric antigen receptor (CAR) T cells have become an important therapeutic option for patients with relapsed and refractory B cell malignancies. However, a significant portion of patients still do not benefit from the therapy owing to various resistance mechanisms, including high expression of multiple inhibitory immune checkpoint receptors. Here, we report a lentiviral two-in-one CAR T approach in which two checkpoint receptors are downregulated simultaneously by a dual short hairpin RNA cassette integrated into a CAR vector. Using this system, we evaluated CD19-targeting CAR T cells in the context of four different checkpoint combinations-PD-1/TIM-3, PD-1/LAG-3, PD-1/CTLA-4, and PD-1/TIGIT-and found that CAR T cells with PD-1/TIGIT downregulation uniquely exerted synergistic antitumor effects. Importantly, functional and phenotypic analyses suggested that downregulation of PD-1 enhances short-term effector function, whereas downregulation of TIGIT is primarily responsible for maintaining a less differentiated/exhausted state, providing a potential mechanism for the observed synergy. The PD-1/TIGIT-downregulated CAR T cells generated from diffuse large B cell lymphoma patient-derived T cells also showed robust antitumor activity and significantly improved persistence in vivo. The efficacy and safety of PD-1/TIGIT-downregulated CD19-targeting CAR T cells are currently being evaluated in adult patients with relapsed or refractory large B cell lymphoma (ClinicalTrials.gov: NCT04836507).
Keywords: CAR T; CD19; PD-1; TIGIT; clinical trial; immune checkpoints; shRNA.
Conflict of interest statement
Declaration of interests C.H.K., Y.-H.L., H.J.L., and Y.L. are inventors on a patent that was filed based on these works. C.H.K. is a co-founder of and holds equity in Curocell Inc. Y.K. is a consultant at Curocell Inc. H.C.K., Y.-H.L., and H.J.L. are employees at Curocell Inc. The remaining authors declare no competing interests.
Copyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.
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Source: PubMed