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Baseline Immune State and T cell Clonal Kinetics are Associated with Response to CAR-T Therapy in Large B-cell Lymphoma

ABSTRACT: Baseline Immune State and T cell Clonal Kinetics are Associated with Response to CAR-T Therapy in Large B-cell Lymphoma

PROVIDER: PRJNA1140521 | ENA |

REPOSITORIES: ENA

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Baseline Immune State and T cell Clonal Kinetics are Associated with Response to CAR-T Therapy in Large B-cell Lymphoma

Project description:Engineered cellular therapy with CD19-targeting chimeric antigen receptor T-cells (CAR-T) has revolutionized outcomes for patients with relapsed/refractory Large B-Cell Lymphoma (LBCL), but the cellular and molecular features associated with response remain largely unresolved. We analyzed serial peripheral blood samples ranging from day of apheresis (day -28/baseline) to 28 days after CAR-T infusion from 50 patients with LBCL treated with axicabtagene ciloleucel (axi-cel) by integrating single cell RNA and TCR sequencing (scRNA-seq/scTCR-seq), flow cytometry, and mass cytometry (CyTOF) to characterize features associated with response to CAR-T. Pretreatment patient characteristics associated with response included presence of B cells and increased lymphocyte-to-monocyte ratio (ALC/AMC). Infusion products from responders were enriched for clonally expanded, highly activated CD8+ T cells. We expanded these observations to 99 patients from the ZUMA-1 cohort and identified a subset of patients with elevated baseline B cells, 80% of whom were complete responders. We integrated B cell proportion and ALC/AMC into a two-factor predictive model and applied this model to the ZUMA-1 cohort. Estimated progression free survival (PFS) at 1 year in patients meeting one or both criteria was 65% versus 31% for patients meeting neither criterion. Our results suggest that patients’ immunologic state at baseline affects likelihood of response to CAR-T through both modulation of the T cell apheresis product composition and promoting a more favorable circulating immune compartment prior to therapy. These baseline immunologic features, measured readily in the clinical setting prior to CAR-T, can be applied to predict response to therapy.

2024-08-12 | GSE273170 | GEO

Clonal kinetics and single cell transcriptional profiling of adoptively transferred CD19-specific CD8+ CAR-T cells in adults with B cell malignancies

Project description:Lymphodepletion chemotherapy followed by infusion of T cells modified to express a CD19-targeting chimeric antigen receptor (CAR) has produced remarkable anti-tumor responses in patients with B cell malignancies. However, little is known about the clonal composition and transcriptional heterogeneity of CAR-T cells in the infusion products (IP) and clonal kinetics after adoptive transfer. We performed single-cell RNA sequencing (scRNA-seq) on CD8+ CAR-T cells isolated from the IP and the blood of patients treated on a phase 1 clinical trial (NCT01865617) with lymphodepletion chemotherapy and a defined formulation of CD4+ and CD8+ CD19-specific CAR-T cells. Infused CD8+ CAR-T cells displayed transcriptional heterogeneity which declined after adoptive transfer, coincident with early expression of genes associated with activation. We identified four transcriptionally distinct CAR-T cell subsets in the IP and found that these subsets differed in their contributions to the CAR-T cell population detected in blood after infusion. Better understanding of the kinetics of clonal expansion of CAR-T cells after adoptive transfer may provide insight into strategies to improve CAR-T cell immunotherapy.

2019-11-22 | GSE125881 | GEO

Baseline immune state and T-cell clonal kinetics are associated with durable response to CAR-T therapy in large B-cell lymphoma.

Project description: Not available

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Two-Stage CAR T-Cell Differentiation in Patients with Large B-Cell Lymphoma

Project description:To investigate the CAR T-cell differentiation in vivo, we performed single-cell, multi-omics analyses of CD28-costimulated CAR T cells from patients with DLBCL who were successfully treated with axicabtagene ciloleucel. Our data shows that CAR T cells undergo two distinct stages of post-infusion clonal expansion.

2025-04-03 | GSE207192 | GEO

Clonal kinetics and single cell transcriptional profiling of adoptively transferred CD19-specific CD8+ CAR-T cells in adults with B cell malignancies

Project description:Clonal kinetics and single cell transcriptional profiling of adoptively transferred CD19-specific CD8+ CAR-T cells in adults with B cell malignancies

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Clonal kinetics and single-cell transcriptional profiling of CAR-T cells in patients undergoing CD19 CAR-T immunotherapy.

Project description: Not available

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Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells

Project description:The choice of costimulatory domain in CAR design dictates the kinetics of in vivo anti-tumor responses, affecting potency, quality and durability. We show that 1928z results in more vigorous effector functions, whereas 19BBz design compensates for their lesser cytotoxic potency by steadily building up their numbers. Therapeutic function can be further improved by combining CD28 and 4-1BB costimulation. 1928z-41BBL was revealed to provide optimal combined costimulation, exhibiting highly therapeutic efficiency with balanced T cell effector function and accumulation. Endogenous IFN-β/IRF7 pathway activation was found in 1928z-41BBL T cell and is required for effector function acquisition. The role of the IFN-β/IRF7 pathway provides a novel mechanism through which engineering T cells improve therapeutic effect by self-providing ‘signal 3’.

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A polyamine-centric blood-based metabolite panel predictive of poor response to CAR T-cell therapy in large B cell lymphoma

Project description:<p>Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (r/r) large B-cell lymphoma (LBCL) results in durable response in only a subset of patients. MYC overexpression in LBCL tumors is associated with poor response to treatment. We tested whether a MYC-driven polyamine signature, as a liquid biopsy, is predictive of response to anti-CD19 CAR-T therapy in patients with r/r LBCL. Elevated plasma acetylated polyamines were associated with non-durable response. Concordantly, increased expression of spermidine synthase, a key enzyme which regulates levels of acetylated spermidine, was prognostic for survival in r/r LBCL. A broad metabolite screen identified additional markers which resulted in a 6-marker panel (6MetP) consisting of acetylspermidine, diacetylspermidine and lysophospholipids which was validated in an independent set from another institution as predictive of non-durable response to CAR T therapy. A polyamine centric metabolomics liquid biopsy panel has predictive value for response to CAR-T therapy in r/r LBCL. </p>

2022-10-31 | MTBLS5381 | MetaboLights

CAR-adapted PIK3CD base editing enhances T cell anti-tumor potency

Project description:Insufficient functional T cell persistence impedes therapeutic success of chimeric antigen receptor (“CAR”) therapies. Here, we performed a CAR-adapted base editing screen of PIK3CD, a key regulator of T cell function, metabolism, and fate. We identified point mutations that beneficially modulate CAR T cell profiles in 4-1BBz and 28z CAR T cells, respectively. Remarkably, point mutations with differing effects on PI3Kδ signaling activity were advantageous in distinct CAR contexts: The PI3Kδ-activating mutation E81K enhanced proliferation, metabolic fitness and effector function in 4-1BBz CARs, promoting long-term functional persistence and enhanced therapeutic efficacy in vivo. Conversely, the PI3Kδ-attenuating mutation L32P improved T cell memory formation and functionality in 28z CAR T cells. Together, our approach of Rational Optimization of Activation-dependent Signaling via Targeted Allelic Reprogramming (ROADSTAR) illustrates the importance of CAR design-specific fine-tuning of tailoring intrinsic T cell signaling and demonstrates the potential of base editing for next-generation cellular therapies.

2025-11-06 | E-MTAB-15746 | biostudies-arrayexpress

IFN-γ-driven iNOS induction in macrophages mediates CAR T cell resistance in B cell lymphoma (CAR-T Metabolites)

Project description:Chimeric antigen receptor (CAR) T cell therapies have revolutionized B cell malignancy treatment, but subsets of patients with large B cell lymphoma (LBCL) experience primary resistance or relapse after CAR T cell treatment. To uncover tumor microenvironment (TME)-induced resistance mechanisms, we examined patients’ intratumoral immune infiltrates and observed that elevated levels of immunoregulatory macrophages in pre-infusion tumor biopsies are correlated with poor clinical responses. In murine models, CAR T cell-produced interferon-gamma (IFN-g) promotes the expression of inducible nitric oxide synthase (iNOS, NOS2) in immunoregulatory macrophages, impairing CAR T cell function. Mechanistically, proteomics analysis of CAR T cells revealed that iNOS-expressing macrophages promote the upregulation of genes mediating apoptosis and cell cycle arrest in CAR T cells, while downregulating ribosome biogenesis and protein synthesis. Furthermore, CAR T cell metabolism is compromised by the depletion of glycolytic intermediates and rewiring of the TCA cycle. Pharmacological inhibition of iNOS enhances the CAR T cell treatment efficacy in B cell tumor-bearing mice. Notably, elevated levels of iNOS+CD14+ monocytes were observed in leukaphereses of patients with non-durable response to CAR T cell therapy. These findings suggest that mitigating iNOS in tumor-associated macrophages (TAMs), potentially by modulating IFN-g expression in CAR T cells, could improve outcomes for LBCL patients.

2026-05-31 | MTBLS14640 | MetaboLights

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