PD-1 and TIGIT downregulation distinctly affect the effector and early memory phenotypes of CD19-targeting CAR T cells
| Autor: | Hyeong Ji Lee, Oded Singer, Jennifer S. Y. Ma, Seok Jin Kim, Won Seog Kim, Hyung Cheol Kim, Youngil Koh, Chan Hyuk Kim, Inkyung Jung, Cedric Hupperetz, Yujean Lee, Young-Ho Lee, Xinxin Wang, Su Kyung Nam |
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| Rok vydání: | 2022 |
| Předmět: |
T-Lymphocytes
Antigens CD19 Programmed Cell Death 1 Receptor Down-Regulation Immunotherapy Adoptive CD19 Small hairpin RNA TIGIT Downregulation and upregulation Drug Discovery Genetics medicine Humans Receptors Immunologic Molecular Biology B cell Pharmacology biology Effector Chimeric antigen receptor Immune checkpoint Phenotype medicine.anatomical_structure Cancer research biology.protein Molecular Medicine Original Article Lymphoma Large B-Cell Diffuse |
| Zdroj: | Mol Ther |
| ISSN: | 1525-0016 |
| DOI: | 10.1016/j.ymthe.2021.10.004 |
| Popis: | 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 ). |
| Databáze: | OpenAIRE |
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