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Nivolumab to restore T-cell fitness in CAR-T refractory multiple myeloma

ABSTRACT: Nivolumab to restore T-cell fitness in CAR-T refractory multiple myeloma

PROVIDER: PRJNA1208466 | ENA |

REPOSITORIES: ENA

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Nivolumab to restore T-cell fitness in CAR-T refractory multiple myeloma

Project description:We here applied single-cell RNA sequencing of circulating T-cells from primary MM patients to perform transcriptional profiling and assess T-cell fitness in the context of emerging resistance to CAR-T cell therapy. Response to PD-1 inhibition after CAR-T was dictated by the fitness state of non-CAR T cells

2025-02-01 | GSE286237 | GEO

Nivolumab to restore T-cell fitness in CAR-T refractory multiple myeloma.

Project description: Not available

| S-EPMC11914164 | biostudies-literature

Single-cell transcriptomic sequencing of BCMA CAR-T cells during CAR-T therapy in refractory primary plasma cell leukemia

Project description:Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the clinical treatment of hematological malignancies due to the prominent anti-tumor effects. B-cell maturation antigen (BCMA) CAR-T cells have demonstrated promising effects in patients with relapsed/refractory multiple myeloma. However, the dynamics of CAR-T cell proliferation and cytotoxicity in a patient remains largely unexplored. Single-cell RNA sequencing samples were collected at three phases: CAR-T products before infusion, CAR-T on day 8 after infusion, and CAR-T on day 15 after infusion. After obtaining the PBMCs for each phase, CAR-T and endogenous T cells were collected by fluorescence-activated cell sorting with anti-Mouse IgG Biotin, FITC Streptavidin, and anti-human CD3 APC.

2020-10-01 | GSE151310 | GEO

Nivolumab treatment for relapsed/refractory Epstein-Barr virus-associated hemophagocytic lymphohistocytosis in adults

Project description:Nivolumab treatment for relapsed/refractory Epstein-Barr virus-associated hemophagocytic lymphohistocytosis in adults

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Restoration of LAT activity improves CAR T-cell sensitivity and persistence in response to antigen-low acute lymphoblastic leukemia

Project description:Chimeric antigen receptor (CAR) T-cells induce responses in patients with relapsed/refractory leukemia; however, long-term efficacy is frequently limited by post-CAR relapses. The inability to target antigen-low cells is an intrinsic vulnerability of second-generation CAR T-cells and underlies the majority of relapses following CD22BBz CAR T-cell therapy. We interrogated CD22BBz CAR signaling in response to low antigen and found inefficient phosphorylation of LAT, limiting downstream signaling. To overcome this, we designed the Adjunctive LAT-Activating CAR T-cell (ALA-CART) platform, pairing a second-generation CAR with a LAT-CAR incorporating the intracellular domain of LAT. ALA-CART cells demonstrated reduced differentiation during manufacturing and increased LAT phosphorylation, MAPK signaling and AP-1 activity. Consequently, ALA-CART cells showed improved cytotoxicity, proliferation, persistence and efficacy against antigen-low leukemias that were refractory to clinically-active CD22BBz CAR T-cells. These data suggest restoration of LAT signaling through the ALA-CART platform represents a promising strategy for overcoming multiple mechanisms of CAR T-cell failure.

2025-05-02 | PXD058699 | Pride

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Project description:Drosophila melanogaster car, carnation, is differentially expressed in 11 experiment(s);

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Project description:Drosophila melanogaster car, carnation, is expressed in 4 baseline experiment(s);

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Nivolumab treatment for relapsed/refractory Epstein-Barr virus-associated hemophagocytic lymphohistocytosis in adults

Project description:Single cell RNA sequencing (scRNA-seq) was performed with peripheral blood cells before (Day 0, T0), during nivolumab treatment (Day 7, T1; Day 21, T2), and when plasma EBV turned negative (Day 76, T3) in 1 patient (patient 7). scRNA-seq libraries were generated following the recommended protocol of the 3’ scRNA-seq 10X genomics platform and using v2 chemistry, and sequenced data was collected by illumina NovaSeq 6000 sequencing.

2019-10-07 | GSE138504 | GEO

Surface proteomics reveals CD72 as a target for in vitro-evolved nanobody-based CAR-T cells in refractory B-cell malignancies

Project description:Alternate strategies are needed for B-cell malignancy patients relapsing after CD19-targeted immunotherapy. Here, integrated cell surface proteomics and epigenetic analysis initially revealed CD72 as an optimal target for poor-prognosis MLL-rearranged B-ALL, which we further found to be expressed widely across B-cell malignancies. Using a recently-described, fully-in vitro system we selected CD72-specific nanobodies, incorporated them into CARs, and demonstrated robust activity against B-cell malignancy models, including CD19 loss. “Antigen escape profiling” modeled membrane proteome changes in the context of CD72 loss while pharmacologic SHIP1 inhibition increased CD72 surface density. We establish CD72-nanobody CAR T’s as a promising therapy for refractory B-cell malignancies.

2022-02-15 | PXD016800 | Pride

Generation of clinical grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of B-cell malignancies

Project description:Long-lived, self-renewing, multipotent T memory stem cells (TSCM) can trigger profound and sustained tumor regression but their rareness poses a major hurdle to their clinical application. Presently, clinically compliant procedures to generate relevant numbers of this T cell population are undefined. Here, we provide a strategy for deriving large numbers of clinical grade tumor-redirected TSCM cells starting from naÃ¯ve precursors. CD8+CD62L+CD45RA+ naÃ¯ve T cells enriched by streptamer-based serial positive selection were activated by CD3/CD28 engagement in the presence of IL-7, IL-21 and the glycogen synthase-3Î² inhibitor TWS119, and genetically engineered to express a CD19-specific chimeric antigen receptor (CD19-CAR). These conditions allowed for the generation of CD19-CAR modified TSCM cells that were phenotypically, functionally and transcriptomically equivalent to their naturally occurring counterpart. Compared with T cell products currently under clinical investigation, CD19-CAR modified TSCM cells exhibit enhanced metabolic fitness, persistence and anti-tumor activity against systemic acute lymphoblastic leukemia xenografts. Based on these findings, we have initiated a phase 1 clinical study to evaluate the activity of CD19-CAR modified TSCM in patients with B-cell malignancies refractory to prior allogeneic hematopoietic stem cell transplantation. Three healthy human blood donors provided lymphocyte-enriched apheresis blood for this study after informed consent. From all samples, total RNA was isolated using an miRNeasy Mini Kit (Qiagen), processed by Ambionâ??s WT expression kit, fragmented and labeled with a WT Terminal Labeling Kit (Affymetrix), hybridized to WT Human Gene 1.0 ST arrays (Affymetrix) and stained on a Genechip Fluidics Station 450 (Affymetrix), all according to the respective manufacturer's instructions. Samples represent exon-level and gene-level analyses.

2016-06-29 | E-GEOD-68003 | biostudies-arrayexpress

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