Decade-long leukemia remissions with persistence of CD4+ CAR T-cells
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PROVIDER: PRJNA841739 | ENA |
REPOSITORIES: ENA
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Project description:Decade-long leukemia remissions with persistence of CD4+ CAR T-cells
| PRJNA841740 | ENA
Project description:The adoptive transfer of T lymphocytes reprogrammed to target tumour cells has demonstrated potential for treatment of various cancers1-7. However, little is known about the long-term potential and clonal stability of the infused cells. Here we studied long-lasting CD19-redirected chimeric antigen receptor (CAR) T cells in two patients with chronic lymphocytic leukaemia1-4 who achieved a complete remission in 2010. CAR T cells remained detectable more than ten years after infusion, with sustained remission in both patients. Notably, a highly activated CD4+ population emerged in both patients, dominating the CAR T cell population at the later time points. This transition was reflected in the stabilization of the clonal make-up of CAR T cells with a repertoire dominated by a small number of clones. Single-cell profiling demonstrated that these long-persisting CD4+ CAR T cells exhibited cytotoxic characteristics along with ongoing functional activation and proliferation. In addition, longitudinal profiling revealed a population of gamma delta CAR T cells that prominently expanded in one patient concomitant with CD8+ CAR T cells during the initial response phase. Our identification and characterization of these unexpected CAR T cell populations provide novel insight into the CAR T cell characteristics associated with anti-cancer response and long-term remission in leukaemia.
| S-EPMC9166916 | biostudies-literature
Project description:Chimeric antigen receptor–T (CAR-T) cell therapies can eliminate relapsed and refractory tumors, but the durability of antitumor activity requires in vivo persistence. Differential signaling through the CAR costimulatory domain can alter the T cell metabolism, memory differentiation, and influence long-term persistence. CAR-T cells costimulated with 4-1BB or ICOS persist in xenograft models but those constructed with CD28 exhibit rapid clearance. Here, we show that a single amino acid residue in CD28 drove T cell exhaustion and hindered the persistence of CD28-based CAR-T cells and changing this asparagine to phenylalanine (CD28-YMFM) promoted durable antitumor control. In addition, CD28-YMFM CAR-T cells exhibited reduced T cell differentiation and exhaustion as well as increased skewing toward Th17 cells. Reciprocal modification of ICOS-containing CAR-T cells abolished in vivo persistence and antitumor activity. This finding suggests modifications to the costimulatory domains of CAR-T cells can enable longer persistence and thereby improve antitumor response.
2020-02-11 | GSE145007 | GEO
Project description:The aim of the study was to compare and contrast cytokine production by CD4+ chimeric antigen receptor + T-cells and putative myeloid derived suppressor cell populations (CD11b+Gr-1 hi and lo) in the spleens of Balb/c mice which had received a transfer of CD19 specific second-generation CAR T-cells 56 days previously following cyclophosphamide pre-conditioning. Splenocytes from four individual mice were pooled, incubated with antibodies to CD4, CD34 (CAR), CD11b, Gr-1 and sorted using flow cytometric cell sorting for CD4+CD34+, Gr-1 and the negative cell fraction. Total RNA was isolated and samples loaded in duplicate in the array. Data was normalized to global expression levels.
2014-02-06 | E-GEOD-54696 | biostudies-arrayexpress
Project description:Multiple myeloma is characterized by frequent clinical relapses following conventional therapy. Recently, chimeric antigen receptor T (CAR-T) cells targeting B-cell maturation antigen (BCMA) has been established as a treatment for patients with relapsed or refractory disease. However, while >70% of patients initially respond to this treatment, clinical relapse and disease progression occurs in most cases. Recent studies showed persistent expression of BCMA at the time of relapse, indicating that immune intrinsic mechanisms may contribute to this resistance. While there were no pre-existing T cell features associated with clinical outcomes, we found that patients with a durable response to CAR-T cell treatment had greater persistence of their CAR-T cells compared to patients with transient clinical responses. They also possessed a significantly higher proportion of CD8+ T effector memory cells. In contrast, patients with short-lived responses to treatment have increased frequencies of cytotoxic CD4+ CAR-T cells. These cells expand in vivo early after infusion but express exhaustion markers (HAVCR2 and TIGIT) and remain polyclonal. Finally, we demonstrate that non-classical monocytes are enriched in the myeloma niche and may induce CAR-T cell dysfunction through mechanisms that include TGFβ. These findings shed new light on the role of cytotoxic CD4+ T cells in disease progression after CAR-T cell therapy.
2024-07-29 | GSE246342 | GEO
Project description:Multiple myeloma is characterized by frequent clinical relapses following conventional therapy. Recently, chimeric antigen receptor T (CAR-T) cells targeting B-cell maturation antigen (BCMA) has been established as a treatment for patients with relapsed or refractory disease. However, while >70% of patients initially respond to this treatment, clinical relapse and disease progression occurs in most cases. Recent studies showed persistent expression of BCMA at the time of relapse, indicating that immune intrinsic mechanisms may contribute to this resistance. While there were no pre-existing T cell features associated with clinical outcomes, we found that patients with a durable response to CAR-T cell treatment had greater persistence of their CAR-T cells compared to patients with transient clinical responses. They also possessed a significantly higher proportion of CD8+ T effector memory cells. In contrast, patients with short-lived responses to treatment have increased frequencies of cytotoxic CD4+ CAR-T cells. These cells expand in vivo early after infusion but express exhaustion markers (HAVCR2 and TIGIT) and remain polyclonal. Finally, we demonstrate that non-classical monocytes are enriched in the myeloma niche and may induce CAR-T cell dysfunction through mechanisms that include TGFβ. These findings shed new light on the role of cytotoxic CD4+ T cells in disease progression after CAR-T cell therapy.
2024-08-07 | GSE274185 | GEO
Project description:transcriptional profiling was performed on Regnase-1 KO CAR and Regnase-1 TCF-1 DKO CAR T cells isolated 7days after co-transfer into tumor bearing mice. TCF-1 deficiency in Regnase-1 KO CAR T cells led to reduced long-term persistence and memory-like phenotype.
2021-04-07 | GSE155020 | GEO
Project description:Chimeric antigen receptor (CAR)-expressing T-cells induce durable remissions in patients with relapsed/refractory B-cell malignancies. CARs are artificial constructs introduced into mature T-cells conferring a second, non-MHC restricted specificity in addition to the endogenous T-cell receptor (TCR). The impact of TCR activation on CAR T-cell efficacy in vivo has important implications for clinical optimization of CAR T-cell therapy, but cannot be systematically evaluated in xenograft models. Using an immunocompetent, syngeneic murine model of CD19-targeted CAR T-cell therapy for pre-B cell ALL, we demonstrate loss of CD8 CAR T-cell mediated clearance of leukemia associated with T-cell exhaustion and apoptosis when TCR antigen is present. CD4 CAR T-cells demonstrate equivalent cytotoxicity, as compared to CD8 CAR T-cells, and in contrast, retain in vivo efficacy in the presence of TCR stimulation. Gene expression profiles confirm increased exhaustion and apoptosis of CAR8 upon dual receptor stimulation compared to CAR4, and indicate inherent differences in T-cell pathways. Chimeric antigen receptor (CAR) T cells express two activating receptors, the CAR and the endogenous T cell receptor (TCR). CAR T cells can be derived from either CD8 or CD4 T cells to generate CAR8 and CAR4 cells, respectively. In vivo, CAR8 and CAR4 cells respond differently when simultaneously stimulated through the CAR and TCR.
2017-12-31 | GSE103632 | GEO
Project description:In this data set we include expression data from human CD4+ T cells isolated on day 0, 6, 11 and 24 follow anti-CD3/anti-CD28 magnetic bead stimulation and chimeric antigen receptor transduction. 30 samples were submitted. Samples represented three biological replicates of normal donors transduced with various CARs. CARs used were a cMet 28z specific CAR comprised of the IgG4 hinge, CD28 transmembrane and CD28 and CD3zeta intracellular domains. A CD19 CD28 CAR was specific to CD19, and was comprised of a CD8a hinge, CD28 transmembrane and CD28 and CD3zeta intracellular domain. A third CAR, the CD19 BBz, was used that was specific to CD19 was comprised of a CD8a hinge, CD8a transmembrane and 4-1BB and CD3zeta intracellular domains. Expression data was analyzied on day 0, 6, 11 and 24.
2015-01-14 | E-GEOD-64914 | biostudies-arrayexpress
Project description:We compared the second-generation (CD28, 4-1BB) with the third-generation (CD28-4-1BB) carbonic anhydrase IX (CAIX) targeted CAR constructs and investigated the antitumor effect of CAR-T cells with different CD4/CD8 proportion in vivo. The results demonstrated that anti-CAIX G36-4-1BB (BBζ) CAR-T cells exhibited superior efficacy compared to G36-CD28 (28ζ) and G36-CD28-4-1BB (28BBζ) CAR-T cells in a clear cell renal cell carcinoma (ccRCC) skrc-59 cell bearing NSG-SGM3 mouse model. Tumor infiltrating T cells were recovered and profiled via flow cytometry and 10X genomics single cell RNA sequencing (scRNAseq). We found that BBζ CAR-T cells upregulated human leukocyte antigen (HLA) II genes and cytotoxicity associated genes, while, downregulated inhibitory immune checkpoint receptor genes and differentiation of regulatory T cells (Tregs), leading to outstanding therapeutic efficacy in vivo. An increased memory phenotype, an elevated tumor infiltration, and a decrease in exhaustion related genes were observed in the CD4/8 mixture of untransduced T (UNT) cells compared to CD8 only ones, indicating that CD4/8 could be the favored cellular composition for CAR-T cell therapy with long-term persistence. In summary, these findings suggest that anti-CAIX BBζ CAR48 serves as a highly potent clinic translatable cell therapy for ccRCC with enhanced proliferation potential, increased functional capacity, diminished terminal differentiation, as well as durable immune surveillance
2022-02-08 | GSE190964 | GEO