Comparison of axicabtagene ciloleucel and tisagenlecleucel patient CAR-T cell products by single cell RNA sequencing
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PROVIDER: PRJNA1265670 | ENA |
REPOSITORIES: ENA
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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.
2025-07-30 | GSE297676 | GEO
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
Project description:CD19-directed chimeric antigen receptor (CAR) T cells can induce durable remissions in relapsed/refractory large B-cell lymphomas (R/R LBCL), but 60% of patients still relapse. Biological mechanisms explaining lack of disease-response are largely unknown. To identify mechanisms of response and survival before CAR T manufacturing in 95 R/R LBCL receiving tisagenlecleucel or axicabtagene ciloleucel, we performed phenotypic, transcriptomic and functional evaluations of leukapheresis products (LK). Transcriptomic profiling of T cells in LK, revealed a signature composed of 4 myeloid genes able to identify patients with very short progression-free survival, highlighting the role of monocytes in CAR T therapy response. Accordingly, response and survival were negatively influenced by high circulating absolute monocyte counts at the time of leukapheresis, and the combined evaluation of peripheral blood monocytes and the four-gene signature in LK, identifies LBCL patients at very high risk of progression after CAR T.
2024-04-24 | GSE243973 | GEO
Project description:Single-cell dynamics of breakthrough toxicities following anakinra prophylaxis for axicabtagene ciloleucel treatment in lymphoma
| PRJNA1033334 | ENA
Project description:Purpose: To compare cell states amoung three populations of interest among circulating CAR T cells in patients with lymphoma. Methods: Nine patients with large B-cell lymphoma (LBCL) were treated with axicabtagene ciloleucel (axi-cel), a commercial CD19-targeted CAR T-cell therapy. On day 7, fresh peripheral blood mononuclear cells were stained with an antibody panel for fluorescence-activated cell sorting (FACS), a panel for cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq), and a viability dye. Single live CAR+ T cells were sorted from each patient, counted, processed for 5' single-cell RNA-sequencing with feature barcoding and TCR clonotype analysis on the 10X Genomics platform, and sequenced by the Stanford Genomics Facility (HighSeq 4000) or Novogene (NovaSeq 6000). Results: We found that circulating CD4+ and CD8+ CAR T cells that express CD57 and T-bet are clonally expanded and display features of effector T cells. In contrast, CD4+ CD57- CAR T cells that express Helios expand polyclonally and display features of T regulatory cells. Conclusions: This study provides insights into cell states of circulating CAR T cells on day 7 that associate with clinical response or toxicity in LBCL patients treated with axi-cel.
2022-07-28 | GSE168940 | GEO
Project description:BackgroundIn a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after the failure of conventional therapy.MethodsIn this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy. Patients received a target dose of 2×106 anti-CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine. The primary end point was the rate of objective response (calculated as the combined rates of complete response and partial response). Secondary end points included overall survival, safety, and biomarker assessments.ResultsAmong the 111 patients who were enrolled, axi-cel was successfully manufactured for 110 (99%) and administered to 101 (91%). The objective response rate was 82%, and the complete response rate was 54%.With a median follow-up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response. The overall rate of survival at 18 months was 52%. The most common adverse events of grade 3 or higher during treatment were neutropenia (in 78% of the patients), anemia (in 43%), and thrombocytopenia (in 38%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 13% and 28% of the patients, respectively. Three of the patients died during treatment. Higher CAR T-cell levels in blood were associated with response.ConclusionsIn this multicenter study, patients with refractory large B-cell lymphoma who received CAR T-cell therapy with axi-cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events. (Funded by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program; ZUMA-1 ClinicalTrials.gov number, NCT02348216 .).
| S-EPMC5882485 | biostudies-literature
Project description:We present a resource of scRNA-seq and scTCR-seq data from the infusion products of 59 patients with relapsed or refractory large B-cell lymphoma (rrLBCL) treated with standard-of-care axicabtagene ciloleucel (Axi-cel), that we have made publicly available to facilitate ongoing and future discovery efforts that will improve patient outcomes.
2023-08-29 | GSE241783 | GEO
Project description:Gene expression profile of CD22 CAR T-cell products
| PRJNA824016 | ENA
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
Project description:The Tumor Microenvironment and Inflammation Influence toxicity in patients with Large B Cell Lymphoma Treated with Axicabtagene Ciloleucel
| PRJNA642653 | ENA