Background: Axi-cel is a US and EU-approved autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy for pts with relapsed/refractory large B cell lymphoma after 1 prior therapy as a result of ZUMA-7 (NCT. In ZUMA-1 (NCT02348216), the pivotal study which initially led to the approval of axi-cel in the 3L+ setting, the objective response rate was 83% (58% complete response rate; Locke et al. Lancet Oncol. 2019) and at 5 years follow up an OS rate of 42.6%, 5 years durable response and 5 years disease specific survival at 51% ( Neelapu et al. Blood 2023). T cell-related biology (Immunosign 21; Immunoscore®IC) measured pretreatment in the tumor microenvironment (TME) was associated with response to axi-cel ( Scholler et al., 2022). Increased density of activated PD-1+LAG-3+/−TIM-3−CD8+ T cells, measurable pretreatment, facilitates clinical response in pts post-axi-cel. This expanded analysis characterized the impact of axi-cel treatment on the TME immune contexture and examined associations between immune cell subsets and relapse.
Methods: Baseline and post-infusion tumor biopsy samples were analyzed by multiplex immunohistochemistry ( Brightplex®). Four panels were developed and applied to assess T cell infiltration (CD3 CD8 FOXP3 TIM3 PD1 LAG3 TOX), regulatory T cell subtyping (CD3 CD8 GATA3 TBET RORg BCL6), T cell activation & exhaustion (CD3 CD8 TIM3 LAG3 PD1 GZMB KI67), macrophage (CD68 CD64 CD163 CD204 CD206 PDL1) and MDSC (CD3 CD11B CD68 CD14 CD15 LOX1 S100A9) subsets. Transcriptomic analysis was performed using nCounter® Pan Cancer panel. The association between T cell subtypes and macrophages cell subset density, and probability to relapse was evaluated. T test values were based on Brightplex analysis.
Results: 34 tumor biopsies (16 at baseline, 18 post-infusion) from 26 pts were analyzed including 11 relapsed (6 CR/5 PR) and 15 durable response (15 CR). The baseline and post-infusion TME comprised all major macrophages, MDSC and T cell subsets, with diverse distribution across samples analyzed.
Low proinflammatory M1 macrophage density was observed at baseline and post-infusion across patients. In relapsed patients, baseline tumors were enriched with a significantly higher proportion of protumoral M2 macrophage (p<0.0001). A shift of M1-M2 polarization was observed between baseline and post-infusion (Baseline 33%M1M2 / 65%M2, post infusion 76%M1M2 / 21%M2, p<0,0001) across the cohort. In contrast, in relapsed patients, M-MDSC cell density was significantly increased post treatment (p=0.0420). In addition, Innate lymphocyte cells subtype 2 (ILC2) cell density, previously described to be positively correlated with improved overall survival in CRC ( Huang et al. 2021 Cancers), was significantly decreased in relapsed patients post infusion (p=0.019).
Post-infusion, durable response was associated with a significant increase in pan-Macrophages (p=0.0360) and cytotoxic T cell subset densities: CD8 naïve T cells (p=0.016); Activated Cytotoxic T cell (GZMB+)(p=0.0203); PD1+TIM3+LAG3- cytotoxic T cell (p=0.0117); CD8 regulatory T cell (FOXP3+)(p=0.012). Regarding T helper lineage, ongoing response was associated with a significant increase of: CD4 naïve T cells (p=0.021); T helper Th2 (p=0.020); cytotoxic T lymphocyte TC2 and TC1/TC2 cell densities (respectively p=0.0052 and 0.011).
Additional characterization of the immune contexture and correlative analysis of cell subsets will be presented.
Conclusion: These results suggest that baseline proportions of protumor M2 macrophages may predict disease relapse after axi-cel treatment. Following infusion, relapse is also associated with spatial enrichment of M-MDSC, whereas durable response is related to increases in T cell subpopulation densities inclusive of cytotoxic T cells, T helper, TC1/TC2 ratios and innate T-subpopulations. These findings suggest that axi-cel treatment drastically impacts tumor immune mobilization, infiltration and contexture, which correlates with long term response.
Disclosures
Mattie:Kite, a Gilead Company: Current Employment, Current equity holder in publicly-traded company. Grosso:Veracyte: Current Employment, Current equity holder in publicly-traded company. Auguste:Veracyte: Current Employment, Current equity holder in publicly-traded company. Arnaud:Veracyte: Current Employment, Current equity holder in publicly-traded company. Locke:Pfizer: Membership on an entity's Board of Directors or advisory committees; Sana: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite, a Gilead Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional , Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional , Research Funding; Allogene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional ; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Wugen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Umoja: Consultancy, Membership on an entity's Board of Directors or advisory committees; Imedex: Other; CERo Therapeutics: Other: (Institutional); Iovance: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Legend Biotech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society: Other; National Cancer Institute: Other; Society for Immunotherapy of Cancer: Other; Clinical Care Options Oncology: Other; BioPharma Communications CARE Education: Other: Institutional; ASH: Other: Travel Support; Aptitude Health: Other: Travel Support; Emerging Therapy Solutions: Consultancy, Other; Bristol Myers Squibb/ Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional , Research Funding; Caribou: Consultancy; Calibr: Consultancy; Cellular Medicine Group: Consultancy; Cowen: Consultancy; Daiichi Sankyo: Consultancy; EcoR1: Consultancy; GammaDelta Therapeutics: Consultancy; Gerson Lehrman Group (GLG): Consultancy; A2 Biotherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Neelapu:Precision Biosciences: Research Funding; Morphosys: Consultancy, Other: Advisory board member; Sana Biotechnology: Consultancy, Other: Advisory board member, Research Funding; Synthekine: Consultancy, Other: Advisory board member; Athenex: Consultancy, Other: Advisory board member; Fosun Kite: Consultancy, Other: Advisory board member; Sellas Life Sciences: Consultancy, Other: Advisory board member; Allogene: Consultancy, Other: Advisory board member, Research Funding; N/A: Patents & Royalties: Related to cell therapy and the safety switch described (intellectual property); Longbow Immunotherapy: Current holder of stock options in a privately-held company; Janssen: Consultancy, Other: Advisory board member; Chimagen: Consultancy, Other: Advisory board member; Immunoadoptive Cell Therapy Private Limited: Consultancy, Other: Scientific Advisory Board; Merck: Consultancy, Other: Advisory Board Member; Carsgen: Consultancy; Takeda: Consultancy, Other: Advisory board member; Kite, A Gilead Company: Consultancy, Other: Advisory Board Member, Research Funding; Astellas Pharma: Consultancy, Other: Advisory board member; Caribou: Consultancy, Other: Advisory board member; Bluebird Bio: Consultancy, Other: Advisory board member; Orna Therapeutics: Consultancy, Other: Advisory board member; Incyte: Consultancy, Other: Advisory board member; Adicet Bio: Consultancy, Other: Advisory board member, Research Funding; Bristol Myers Squibb: Consultancy, Other: Advisory Board Member, Research Funding. Miklos:Miltenyi: Consultancy, Research Funding; Adicet: Research Funding; Allogene: Research Funding; 2Seventy Bio: Research Funding; Fate Therapeutics: Research Funding; NA: Patents & Royalties: cGVHD patent holder for Ibrutinib as cGVHD therapy but no compensation; A2 Biotherapeutics: Consultancy, Current holder of stock options in a privately-held company, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties: rights to royalties from Fred Hutch for patents licensed to Juno, Research Funding; Legend Biotech: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Mustang Bio: Consultancy, Honoraria; Navan Technologies: Consultancy, Current holder of stock options in a privately-held company, Honoraria; Novartis: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Umoja: Consultancy, Honoraria; Bioline Rx: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Janssen: Consultancy, Honoraria, Other: Travel support. Jacobson:Kite, A Gilead Company: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel support; Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel support; Lonza: Consultancy, Honoraria, Other: Travel support; Ispen: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Bluebird Bio: Consultancy, Honoraria; Instil Bio: Consultancy, Honoraria; ImmPACT Bio: Consultancy, Honoraria; Daiichi Sanko: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Humanigen: Consultancy, Honoraria, Other: Travel support; Nkarta: Consultancy, Honoraria; Precision BioSciences: Consultancy, Honoraria, Other: Travel support; Clinical Care Options: Speakers Bureau; Axis: Speakers Bureau. Ghobadi:BMS: Consultancy; CRISPR Therapeutics: Consultancy; Kite/Gilead: Consultancy, Honoraria, Research Funding; Wugen Inc: Consultancy; Genentech, Inc.: Research Funding; Atara: Consultancy; Amgen: Consultancy, Research Funding. Kim:Gilead Sciences: Current holder of stock options in a privately-held company; Kite, a Gilead Company: Current Employment. Nater:Kite Pharma, a Gilead company: Current Employment, Current equity holder in publicly-traded company. Shen:Kite, a Gilead Company: Current Employment, Current holder of stock options in a privately-held company, Other: Intellectual property , Patents & Royalties; Atara: Other: Intellectual property , Patents & Royalties. Galon:Veracyte: Current Employment.
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