Postinfusion PD-1+ CD8+ CAR T cells identify patients responsive to CD19 CAR T-cell therapy in non-Hodgkin lymphoma

• Published in: Blood advances Vol. 8; no. 12; pp. 3140 - 3153
• Main Authors: Denlinger, Nathan, Song, No-Joon, Zhang, Xiaoli, Jeon, Hyeongseon, Peterson, Chelsea, Wang, Yi, Reynolds, Kelsi, Bolz, Robert M., Miao, Jessica, Song, Chunhua, Wu, Dayong, Chan, Wing Keung, Bezerra, Evandro, Epperla, Narendranath, Voorhees, Timothy J., Brammer, Jonathan, Kittai, Adam S., Bond, David A., Sawalha, Yazeed, Sigmund, Audrey, Reneau, John C., Rubinstein, Mark P., Hanel, Walter, Christian, Beth, Baiocchi, Robert A., Maddocks, Kami, Alinari, Lapo, Vasu, Sumithira, de Lima, Marcos, Chung, Dongjun, Jaglowski, Samantha, Li, Zihai, Huang, Xiaopei, Yang, Yiping
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 25.06.2024; The American Society of Hematology
• Subjects: Immunobiology and Immunotherapy
• ISSN: 2473-9529; 2473-9537; 2473-9537
• DOI: 10.1182/bloodadvances.2023012073

•After CAR T-cell infusion, circulating PD-1+ CAR+ CD8+ T cells are highly associated with response to CAR T-cell therapy for NHL.•Spectral flow analysis reveals specific populations of stem-like and effector-like CAR T cells, which correlate with improved outcomes. [Display omitted] Chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment for relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). Robust biomarkers and a complete understanding of CAR T-cell function in the postinfusion phase remain limited. Here, we used a 37-color spectral flow cytometry panel to perform high dimensional single-cell analysis of postinfusion samples in 26 patients treated with CD28 costimulatory domain containing commercial CAR T cells for NHL and focused on computationally gated CD8+ CAR T cells. We found that the presence of postinfusion Programmed cell death protein 1 (PD-1)+ CD8+ CAR T cells at the day 14 time point highly correlated with the ability to achieve complete response (CR) by 6 months. Further analysis identified multiple subtypes of CD8+ PD-1+ CAR T cells, including PD-1+ T cell factor 1 (TCF1)+ stem-like CAR T cells and PD-1+ T-cell immunoglobulin and mucin-domain containing-3 (TIM3)+ effector-like CAR T cells that correlated with improved clinical outcomes such as response and progression-free survival. Additionally, we identified a subset of PD-1+ CD8+ CAR+ T cells with effector-like function that was increased in patients who achieved a CR and was associated with grade 3 or higher immune effector cell–associated neurotoxicity syndrome. Here, we identified robust biomarkers of response to CD28 CAR T cells and highlight the importance of PD-1 positivity in CD8+ CAR T cells after infusion in achieving CR.