CAR-T Cell Subsets and Immune Repertoire Are Associated with Immune-Related Adverse Events and Efficacy after CD19 CAR T-Cell Therapy in B Cell Lymphoma

• Published in: Blood 2024-11, Vol.144, p.2053-2053
• Main Authors: Foureau, David M, Guo, Fei, Broemsen, Erik, Jones, Tahj, Ivanina-Foureau, Anna, Jacobs, Ryan, Hu, Bei, Moyo, Tamara K, Pang, Yifan, Park, Steven I., Druhan, Lawrence J., Bell, Ariel, Ghosh, Nilanjan
• Format: Article
• Language: English
• ISSN: 0006-4971
• DOI: 10.1182/blood-2024-205720

Background. CAR T-cell therapy is a potentially curative treatment in relapsed or refractory B-cell lymphoma (BCL). However, most CAR T cell recipients develop immune-related adverse events (irAEs) and around 60% of patients have relapse. We aimed to evaluate the characteristics of CD19-CAR T product(s) expansion during treatment, T cell and immune suppressors contributions to CAR T efficacy and toxicity. Methods. Patients with BCL receiving standard-of-care CAR T-cell therapy were enrolled in an IRB approved study. We evaluated cryopreserved blood samples collected before lymphodepletion (LDC) and at days 2, 8, 15 and 1 month after CAR T cell infusion. Each sample was evaluated by flow cytometry coupled with Uniform Manifold Approximation Projection dimensionality reduction and PhenoGraph clustering. We surveyed the characteristics of CD19CAR+ and CD19CAR- T cell subpopulations, including differentiation (CD45RA, CD62L), activation (CD69, CD25, HLA-DR), proliferation (CD71) and fitness (PD1, Tim3, LAG3) of CD4+ and CD8+ subsets. We also analyzed immune suppressors: polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC: CD11b+ CD33+ HLA-DR-/low IL-4R+ CD15+) and regulatory T cells (Treg: CD4+, CD25high, CD127low). Clinical response at 1 and 6 months, incidence and severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were recorded. We tested putative association between CAR and non-CAR T cell subsets, reported as mean ± standard error, and clinical outcomes using mixed-model analyses with Geisser-Greenhouse correction and Mann-Whitney U test. Results. Forty-two patients (38 large BCL, 4 mantle cell lymphoma) were enrolled; 25 received axi-cel, 13 liso-cel and 4 brexu-cel. Median age was 62.7 (range 27-83) years, 31% were female. We identified 32 immune clusters including 2 CAR T cell subsets detected across all CAR T products: activated/proliferating CD4+ effector memory (EM)-CAR T cell and activated/proliferating CD8+ EM CAR T. These two CAR T cell subsets shared a peak expansion at 8 days post CAR T (CD4+ EM CAR T 4.3±0.9% total T cells; CD8+ EM CAR T 12.7±2.1% of total T cells). Twenty-nine patients (69%) experienced CRS [grade (Gr) 1-2]. Patients who developed CRS displayed a more robust CD4+ EM CAR T cells expansion 8 days post-CAR T (CRS 5.5±1.1% vs no CRS 1.2±0.3%, p