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Cellular and molecular mechanisms determining allogeneic CAR T cell rejection and expansion -- Submission 1 of 2 (Bulk TCR)

ABSTRACT: Allogeneic CAR T cells could overcome limitations of autologous therapies but are limited by immune rejection. We evaluated 11 patients with large B-cell lymphoma treated with a single lot of cemacabtagene ansegedleucel (cema-cel), an allogeneic anti-CD19 CAR T product. Despite receiving identical infusion products, patients exhibited heterogeneous cema-cel expansion and clinical outcomes. Our integrated analyses using longitudinal TCRβ sequencing, single-cell molecular profiling, and mixed lymphocyte reaction assays revealed that high frequencies of pre-existing, recipient-derived alloreactive CD8+ T cells mediated rapid CAR T rejection in non-expanders. Furthermore, effector-like features, rather than stem/central memory programs, drove robust clonal CAR T expansion consistently across expanders. We confirmed similar expansion patterns in two independent cohorts treated with a separate lot of cema-cel or an allogeneic anti-BCMA CAR T product. These findings highlight distinct cell-extrinsic and cell-intrinsic mechanisms that influence allogeneic CAR T performance and provide insights to optimize donor selection, manufacturing, and product design.

ORGANISM(S): Homo sapiens

PROVIDER: GSE345888 | GEO | 2026/09/23

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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Cellular and molecular mechanisms determining allogeneic CAR T cell rejection and expansion -- Submission 1 of 2 (Bulk TCR)

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