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Single-cell sequencing of T cells harvested 4 hours after preparation by different methods

ABSTRACT: We successfully develop a two-in-one approach to generate non-viral genome specific targeted CAR T cells through CRISPR/Cas9. In the adoptive therapy for relapsed/refractory aggressive B-cell non-Hodgkin lymphoma, we observed durable responses without serious adverse events and complete remission in patients treated with these PD1 knockout CAR T cells. Here we applied single-cell sequencing to analyze the characteristcis of T cells harvested 4 hours after preparation by different methods.

ORGANISM(S): Homo sapiens

PROVIDER: GSE201035 | GEO | 2022/06/20

REPOSITORIES: GEO

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Single-cell sequencing of T cells prepared by different methods

Project description:We successfully develop a two-in-one approach to generate non-viral genome specific targeted CAR T cells through CRISPR/Cas9. In the adoptive therapy for relapsed/refractory aggressive B-cell non-Hodgkin lymphoma, we observed durable responses without serious adverse events and complete remission in patients treated with these PD1 knockout CAR T cells. Here we applied single-cell sequencing to analyze the characteristcis of T cells prepared by different methods.

2022-06-20 | GSE186596 | GEO

Single-cell sequencing of infusion products and T cells after administration of non-viral PD1-targeted anti-CD19 CAR T cells

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Immunometabolic determinants of long-term response in leukemia patients receiving CD19 CAR T cell therapy

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2025-06-05 | GSE298663 | GEO

Single-cell sequencing of T cells harvested 4 hours after preparation by different methods

Project description:Single-cell sequencing of T cells harvested 4 hours after preparation by different methods

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Longitudinal single-cell immunoprofiling links durable CAR T response to sustained activation and clonotypic expansion of the native cytotoxic T cell repertoire

Project description:CD19-directed chimeric antigen receptor (CAR) T-cell therapy has transformed outcomes for patients with relapsed/refractory large B-cell lymphoma (LBCL), yet the mechanisms underlying durable remission remain incompletely understood. While CAR T-cell persistence is associated with response, long-term remission can occur despite rapid CAR T clearance, suggesting the involvement of additional immune mechanisms. To investigate the role of the native T-cell repertoire in shaping response durability, we performed single-cell RNA and TCR sequencing (scRNA-seq/scTCR-seq) on longitudinal peripheral blood samples from LBCL patients treated with axicabtagene ciloleucel (axi-cel) in the ZUMA-1 trial. We compared immune landscapes and clonotypic dynamics among patients achieving durable remission (>1 year), those experiencing early relapse (<6 months), and those with refractory disease. Patients with long-term remission exhibited increased cytotoxic, proinflammatory, and proliferative native T-cell subsets, while early relapse was associated with immunoregulatory populations that may suppress T-cell activation. TCR profiling revealed robust clonotypic expansion of native cytotoxic T cells post-infusion in durable responders, with expansion patterns strongly predicting clinical outcomes. Notably, TCR screens did not identify known viral targets, suggesting tumor-specific immunity may mediate ongoing remission. These findings propose native T-cell clonotypic expansion as a key determinant of durable response to CAR T therapy and highlight its predictive potential for long-term clinical outcomes.

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UPenn CAR T cell Responders and Non-responders

Project description:<p>The adoptive transfer of autologous T cells genetically modified to express a CD19-specific, 4-1BB/CD3zeta-signaling chimeric antigen receptor (CAR; CTL019) has shown remarkable activity in patients with B acute lymphoblastic leukemia. Similar therapy can induce long-term remissions for relapsed/refractory chronic lymphocytic leukemia (CLL) patients, but in only a small subset of subjects. The determinants of response and resistance to CTL019 therapy of CLL are not fully understood. We employed next generation sequencing of RNA (RNA-seq) to identify predictive indicators of response to CTL019 treatment. We performed RNA-seq on leukapheresis and manufactured infusion product T cells from patients with heavily pre-treated and high-risk disease. To characterize potency, we also performed RNA-seq on the cellular infusion product after CAR-specific stimulation. Our findings indicate that durable remission in CLL is associated with gene expression signatures of early memory T cell differentiation (e.g., STAT3), while T cells from poorly- or non-responding patients exhibited elevated expression of key regulators of late memory as well as effector T cell differentiation, apoptosis, aerobic glycolysis, hypoxia and exhaustion. These gene expression signatures, along with additional immunological biomarkers, may be used to identify which patients are most likely to respond to cellular therapies and suggest manufacturing modifications that might potentiate the generation of maximally efficacious infusion products.</p>

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Project description:BCMA is the main target for CAR-T cells in multiple myeloma (MM), demonstrating promising outcomes. However, unlike what happens with CART19 in lymphoblastic leukemia and non-hodgkin lymphoma, a high proportion of patients will relapse after CART BCMA therapy due to insufficient antigen expression, low CAR-T cell persistence and/or T-cell exhaustion. CD28 transmembrane domains (CD28-TMD) in CAR receptors promote dimerization with CD28, forming CAR-CD28 heterodimers that enhance sensitivity to low-abundance antigens. In other B cell malignancies, second-generation anti-CD19 4-1BB CARs with CD28-TMD have shown high efficacy and a favorable toxicity profile. We have developed a second-generation CD8α-TMD BCMA-4-1BBζ CAR-T product, ARI0002h (ARI2h; cesni-cel) for patients with relapsed/refractory MM. We hypothesized that replacing the TMD of ARI0002h with a CD28-TMD could increase efficacy and reduce tumor escape while maintaining a tolerable toxicity profile. We generated CAR-T cells using T-cells isolated from buffy coats and evaluated the efficacy and fitness of CAR-Ts at day 8-10 of expansion against several MM cell lines. In vitro analyses included cytotoxicity, proliferation, cytokine secretion, T-cell subset markers, activation and exhaustion profiling, metabolomic assays, and RNA-seq after multiple tumor challenges. In in vivo xenograft studies using NSG mice, with tumor cells expressing GFP-ffLuc, disease progression was monitored weekly via bioluminescence imaging.

2026-03-11 | GSE289423 | GEO

Single-cell profiling identifies pre-existing CD19-negative subclones in a B-ALL patient with CD19-negative relapse after CAR-T therapy

Project description:Chimeric antigen receptor T cell (CAR-T) targeting the CD19 antigen represents an innovative therapeutic approach to improve the outcome of relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). Yet, despite a high initial remission rate, CAR-T therapy ultimately fails for some patients. Notably, around half of relapsing patients develop CD19 negative (CD19neg) B-ALL allowing leukemic cells to evade CD19-targeted therapy. Herein, we investigate leukemic cells of a relapsing B-ALL patient, at two-time points: before (T1) and after (T2) anti-CD19 CAR-T treatment. We show that at T2, the B-ALL relapse is CD19 negative due to the expression of a non-functional CD19 transcript retaining intron 2. Then, using single-cell RNA sequencing (scRNAseq) approach, we demonstrate that CD19neg leukemic cells were present before CAR-T cell therapy and thus that the relapse results from the selection of these rare CD19neg B-ALL clones. In conclusion, our study shows that scRNAseq profiling can reveal pre-existing CD19neg subclones, raising the possibility to assess the risk of targeted therapy failure.

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