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Pre-Treatment peripheral Immune composition can accurately predict CAR-T outcomes in patients with Large B-Cell Lymphoma

ABSTRACT: Chimeric Antigen Receptor (CAR)-T cell therapy has revolutionized the treatment landscape for relapsed/refractory B-cell lineage malignancies. Yet, about 50% of patients fail to respond. Refined patient selection criteria and response prediction, would contribute to improved prognosis and safer treatments. We performed single-cell RNA sequencing of pre-treatment peripheral blood samples from 42 Diffuse Large B-Cell patients, receiving anti CD-19 CAR-T products: axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) and correlated their molecular and cellular features with treatment outcome at three months post-infusion. Responders tended to have fewer regulatory T cells (Tregs), and exhibited lower cellular activation and stress pathway expression in T and NK cells. Responders had higher levels of CD16 monocytes and dendritic cells, while non-responders displayed increased myeloid cell apoptosis and pro-inflammatory gene expression. All patients with B-cells at leukapheresis (13/42) responded completely, including six with malignant B-cells showing immunoglobulin light chain clonality and DLBCL-typical genetic aberrations. These insights enabled us to craft a machine-learning prediction model based on pre-leukapheresis blood composition. Our findings highlight the cellular and molecular milieu required for a successful CAR-T outcome, and provide a framework for practical personalized tools for patient selection and stratification for improved prognosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE267097 | GEO | 2025/09/14

REPOSITORIES: GEO

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Project description:Background: Autologous CD19 CAR T cell therapy leads to durable responses and improved survival in patients with relapsed or refractory large B cell lymphoma (R/R LBCL). Among approved CAR T cell products, axicabtagene ciloleucel (axi-cel; CD19/CD28) has greater real-world efficacy and cytokine-associated toxicity than tisagenlecleucel (tisa-cel; CD19/4-1BB), for reasons that are poorly understood. Methods: Here we report single cell RNA sequencing (scRNA-seq) of 57 pre-infusion CAR T cell products from axi-cel (n=39) and tisa-cel (n=18) patients treated as standard-of-care for R/R LBCL, and their biological associations with clinical outcomes. In vitro CAR manufacturing conditions mimicking those known for axi-cel and tisa-cel were performed using CD19/CD28z or CD19/4-1BBz constructs. Results: ScRNA-seq revealed that axi-cel and tisa-cel are markedly different products. Axi-cel is comprised of more CD4 central memory, CD8 central memory, and CD8 effectors, whereas tisa-cel is comprised of more proliferative CD4 and CD8 cells. Across multiple T cell subsets, axi-cel had greater expression of immune response pathways and protein synthesis and trafficking pathways vs. tisa-cel. On comparison of infusion product CAR transgene-positive (CAR+) cells to CAR transgene-negative (CAR-) T cells, axi-cel CAR+ cells had vastly different gene expression than axi-cel CAR- cells. Unexpectedly, tisa-cel CAR+ cells were highly similar to tisa-cel CAR- cells. Under recapitulated CAR-T manufacturing conditions known to be utilized for axi-cel and tisa-cel, we found that CAR+ cells differed from CAR- cells early after manufacturing yet became more similar to CAR- cells after prolonged expansion. Prolonged time in expansion culture, as utilized during tisa-cel manufacturing, greatly decreased naïve and central memory T cell subsets. Conclusions: Following manufacture, axi-cel is less differentiated and has greater immune activation compared to tisa-cel, potentially accounting for its greater efficacy and toxicity in patients. Our data support the conclusion that tisa-cel is adversely affected by its manufacturing rather than by the CAR construct.

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Pre-Treatment peripheral Immune composition can accurately predict CAR-T outcomes in patients with Large B-Cell Lymphoma

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