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Sequencing analysis of CAR T cell products and apheresis cells in DLBCL patients treated with tandemCAR-T cell

ABSTRACT: In this study, 58 r/r DLBCL patients treated with tandem CD19/CD20 CAR T cells. Twenty-seven patients had durational responses for more than 24 months, and the median PFS was 21.7 months. But 15 patients still did not have an objective response, and 11 patients relapsed within 1 year. The analysis found that CD8+TSCM cells with higher frequency and stronger activation ability in CART products were the key to achieving clinical sustained objective response. Bulk RNA-Seq and single-cell RNA-Seq then were performed on CAR-T cell products and pre-manufacture T cells of patients with DLBCL. We note that a CD8+ stem cell-like memory T cell population with a higher proportion and stronger activating capacity of the CAR-T cell products was key to achieving durable clinical response. By analyzing autologously-derived, pre-manufacture T cells, our data suggest that heterogeneity in the cellular and molecular features of pre-manufacture T cells contribute to the variation in efficacy after CAR-T cell therapy in DLBCL. The differences in anti-tumour efficacy of CAR-T cells among patients with different clinical outcomes appear to be due to the loss of CCR7 gene expression accompanied by increased expression of activation- and inhibitor-related genes in the CD8+ naïve-T cell populations among the apheresis T cells from patients with a poor molecular response. These findings significantly advance our understanding of the underlying molecular determinants of pre-manufacture T cell function.

ORGANISM(S): Homo sapiens

PROVIDER: GSE243325 | GEO | 2023/11/09

REPOSITORIES: GEO

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Project description:Background and methods: CD19-directed CAR T-cell therapy (CAR-T) has emerged as a promising treatment modality for multiple B-cell malignancies. However, its utility is hampered by a unique toxicity profile that classically includes cytokine release syndrome (CRS) and neurotoxicity. Hematological toxicity represents a vexing and common side effect. Cytopenia can occur long after lymphodepleting chemotherapy and resolution of CRS and is often prolonged and biphasic in nature. Some patients have been described to develop severe bone marrow (BM) failure, which can predispose for severe infections and high non-relapse mortality. Overall, the underlying pathomechanisms of CAR-T-related hematotoxicity remain poorly understood. We performed flow cytometry, serum cytokine profiling, single cell transcriptome and TCR-sequencing of PBMCs from pre-/post-treatment sampels of a patient with DLBCL-type Richter Transformation receiving tisagenlecleucel in a standard-of-care setting and present one marrow failure. Results: The advent of chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape of refractory B-cell malignancies. Real-world evidence has highlighted the high incidence of hematological toxicity, including prolonged and profound cytopenia. Here, we present the case of bone marrow failure in a 57-year old man with DLBCL-type Richter Transformation receiving tisagenlecleucel in a standard-of-care setting. The clinical course was notable for underlying bone marrow infiltration, severe cytokine release syndrome and multiple infectious complications in the setting of prolonged, profound neutropenia. Cytokine profiling revealed a signature consistent with acquired aplastic anemia – including downregulation of CD40-L and EGF. Flow cytometric analyses demonstrated expansion of both CAR and non-CAR bearing CD8+ CD57+ T-cells in the bone marrow, an immunophenotype linked to oligoclonality in aplastic anemia. On a single-cell level, this was accompanied by T-cell receptor Vβ oligoclonal expansion and post-CAR clonal drift. Gene expression profiling revealed upregulation of exhaustion markers on (CAR) T-cells and decreased expression of genes involved in STAT signalling and inflammatory response. Conclusion: In conclusion, this case highlights the complex nature of CAR-T-related hematological toxicity and introduces oligoclonal (CAR) T-cell expansion as a potential contributing pathomechanism.

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Sequencing analysis of CAR T cell products and apheresis cells in DLBCL patients treated with tandemCAR-T cell

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