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2053 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

Program: Oral and Poster Abstracts
Session: 702. CAR-T Cell Therapies: Basic and Translational: Poster I
Hematology Disease Topics & Pathways:
Adult, Lymphomas, B Cell lymphoma, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Diseases, Treatment Considerations, Biological therapies, Immunology, Lymphoid Malignancies, Adverse Events, Biological Processes, Technology and Procedures, Profiling, Study Population, Human
Saturday, December 7, 2024, 5:30 PM-7:30 PM

David M Foureau1, Fei Guo, PhD1*, Erik Broemsen, PhD1*, Tahj Jones1*, Anna Ivanina-Foureau, PhD1*, Ryan Jacobs2, Bei Hu, MD2, Tamara K Moyo, MD2*, Yifan Pang, MD2, Steven I. Park, MD2, Lawrence J. Druhan, PhD3, Ariel Bell, MPH3* and Nilanjan Ghosh, MD, PhD2

1Levine Cancer Institute, Atrium Health, Charlotte, NC
2Department of Hematologic Oncology and Blood Disorders, Atrium Health Levine Cancer Institute, Charlotte, NC
3Hematology Oncology Translational Research Laboratory, Atrium Health Levine Cancer Institute, Charlotte, NC

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<0.01). There was trend to association of CD4+ EM CAR T expansion with response to CAR T therapy at 1 month (CR/PR 4.5±1.1% vs PD 2.2±1.3%, p<0.1). The CAR T product (any grade CRS: axi-cel 76% vs liso-cel 46%, p<0.1) and higher prevalence of late activated CD4+ EM T cells pre-LDC (CRS 3.4±0.9% vs no CRS 1.9±0.4%, p<0.05) were both associated with a heightened risk of CRS. Conversely, patients who had higher immune suppressors prior to or 2-3 days post-CAR T developed no or lower grade CRS (PMN-MDSChigh 0.7±0.2 vs Treghigh 0.4±0.2 vs immune suppressorlow 1.5±1.3 average CRS grade; p<0.01) suggesting immune contexture may mitigate CRS risks.

Nineteen patients (36.5%) developed ICANS (3 Gr1, 6 Gr2, 7 Gr3, 2 Gr4, 1 Gr5). Patients who developed ICANS had strong CD8+ EM CAR T cell expansion 8 days post CAR T (ICANS 17.5±3.8% vs no ICANS 7.9±1.3%, p<0.01). There was a trend that CD8+ EM CAR T cell expansion was associated with response to CAR T therapy at 1 month (CR/PR 14.4±2.5% vs PD 4.4±1.7%, p<0.1). Higher prevalence of late activated CD8+ EM T cell pre-LDC was also associated with an increased risk of ICANS (ICANS 3.7±0.8% vs no ICANS 1.7±0.5%, p<0.01). Conversely patients with a higher prevalence of resting (p<0.01) or early activated (p<0.05) CD8+ effector T cells pre-lymphodepletion were more likely to achieve a sustained complete response to CAR T-cell therapy at 6 months.

Conclusions. Immune profiling of patients who received CAR T-cell therapy for BCL revealed two distinct CAR T subsets associated with response and irAEs associated with CD19 CAR T cell therapy. Overall, our data show that CD4+ EM CAR T cells expansion is associated with CRS and early response while CD8+ EM CAR T cells have more prominent roles in ICANS and sustained response. Furthermore, T cell fitness pre-LDC may be a key parameter behind the CAR T-cell therapy response/toxicity dichotomy with resting/early activated T cells linked to response and late activated T cells to irAEs.

Disclosures: Foureau: Astrazeneca: Research Funding. Jacobs: AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Regeneron: Research Funding; SecuraBio: Consultancy; Adaptive: Speakers Bureau; AbbVie: Consultancy, Research Funding, Speakers Bureau; Beigene: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Research Funding; Genentech: Consultancy; Janssen: Consultancy; Lilly: Consultancy, Research Funding; Galapagos: Consultancy. Hu: Janssen Biotech, Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc./F. Hoffmann-La Roche Ltd, BMS, BeiGene: Research Funding; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Other: Steering committee on clinical trial (GO43643). Moyo: Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Genmab: Research Funding; J&J: Research Funding; Century Therapeutics: Research Funding. Park: BMS: Consultancy, Research Funding; Pfizer, Seattle Genetics: Consultancy, Research Funding; Epizyme: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees. Ghosh: BeiGene: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Genmab: Consultancy; Abbvie: Consultancy, Speakers Bureau; Adaptive Biotech: Consultancy; ADC Therapeutics: Consultancy; Gilead/Kite: Consultancy, Speakers Bureau; Incyte: Consultancy; Janssen: Consultancy, Speakers Bureau; Lava Therapeutics: Consultancy.

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