High-specificity CRISPR-mediated genome engineering in CB-011, an anti-BCMA allogeneic CAR-T cell, suppresses allograft rejection in preclinical models
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1048509 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27051100.fastq.gz | Fastqsanger.gz | |||
| SRR27051101.fastq.gz | Fastqsanger.gz | |||
| SRR27051102.fastq.gz | Fastqsanger.gz | |||
| SRR27051103.fastq.gz | Fastqsanger.gz | |||
| SRR27051104.fastq.gz | Fastqsanger.gz |
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Project description:Allogeneic chimeric antigen receptor (CAR)-T cell therapies hold the potential to overcome many of the challenges associated with patient-derived (autologous) CAR-T cells. Key considerations in the development of allogeneic CAR-T cell therapies include prevention of GvHD and suppression of allograft rejection. Here we describe preclinical data supporting the ongoing first-in-human clinical trial (CaMMouflage) in relapsed/refractory multiple myeloma patients evaluating CB-011, a hypoimmunogenic, allogeneic anti–B cell maturation antigen (BCMA) CAR-T cell therapy candidate. CB-011 cells feature 4 genomic alterations and were engineered from healthy donor-derived T cells using a Cas12a CRISPR hybrid RNA-DNA (chRDNA) genome-editing technology platform. To address allograft rejection, CAR-T cells were engineered to prevent endogenous human leukocyte antigen (HLA) class I complex expression and overexpress a single-chain polyprotein complex composed of beta-2 microglobulin (B2M) tethered to HLA-E. Additionally, T cell receptor expression was disrupted at the T cell receptor alpha constant locus in combination with the site-specific insertion of a humanized BCMA-specific CAR. CB-011 cells exhibited robust plasmablast cytotoxicity in vitro in a mixed lymphocyte reaction in cell co-cultures derived from patients with multiple myeloma. Additionally, CB-011 cells demonstrated suppressed recognition by and cytotoxicity from HLA-mismatched T cells. CB-011 cells were protected from natural killer (NK) cell–mediated cytotoxicity in vitro and in vivo due to endogenous promoter-driven expression of B2M–HLA-E. Potent antitumor efficacy, when combined with an immune-cloaking armoring strategy to dampen allograft rejection, offers optimized therapeutic potential in multiple myeloma.
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Project description:Self-reactive antibodies cloned from B cells infiltrating in a human renal allograft were subjected to IP-mass spectrometry using nuclear lysates of HEp-2 cells.
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Project description:Allogeneic chimeric antigen receptor (CAR) T cell therapies hold the potential to overcome many of the challenges associated with patient-derived (autologous) CAR T cells. Key considerations in the development of allogeneic CAR T cell therapies include prevention of graft-vs-host disease (GvHD) and suppression of allograft rejection. Here, we describe preclinical data supporting the ongoing first-in-human clinical study, the CaMMouflage trial (NCT05722418), evaluating CB-011 in patients with relapsed/refractory multiple myeloma. CB-011 is a hypoimmunogenic, allogeneic anti-B-cell maturation antigen (BCMA) CAR T cell therapy candidate. CB-011 cells feature 4 genomic alterations and were engineered from healthy donor-derived T cells using a Cas12a CRISPR hybrid RNA-DNA (chRDNA) genome-editing technology platform. To address allograft rejection, CAR T cells were engineered to prevent endogenous HLA class I complex expression and overexpress a single-chain polyprotein complex composed of beta-2 microglobulin (B2M) tethered to HLA-E. In addition, T-cell receptor (TCR) expression was disrupted at the TCR alpha constant locus in combination with the site-specific insertion of a humanized BCMA-specific CAR. CB-011 cells exhibited robust plasmablast cytotoxicity in vitro in a mixed lymphocyte reaction in cell cocultures derived from patients with multiple myeloma. In addition, CB-011 cells demonstrated suppressed recognition by and cytotoxicity from HLA-mismatched T cells. CB-011 cells were protected from natural killer cell-mediated cytotoxicity in vitro and in vivo due to endogenous promoter-driven expression of B2M-HLA-E. Potent antitumor efficacy, when combined with an immune-cloaking armoring strategy to dampen allograft rejection, offers optimized therapeutic potential in multiple myeloma. See related Spotlight by Caimi and Melenhorst, p. 385.
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Project description:Acute allograft rejection is a leading cause for the failure of organ allotransplantation. Identifying the genes involved in the rejection process provides clues to study the mechanisms, and to provide specific gene targets for monitoring, predicting and preventing acute allograft rejection. Using a mice model of skin acute allograft rejection and SAGE method, we analyzed gene expression in the CD4+ T cells of the mice, the cell type known to play critical roles in acute allograft rejection. Our study identifies 402 SAGE tags significantly different from these from the control. From these SAGE tags, we identified 91 increasingly and 85 decreasingly expressed genes, and many genes have not been linked with acute allograft rejection before. Functional classification of these genes shows that apoptosis, transcription regulation, cell growth and maintenance and signal transduction are among the most frequently changed functional groups. Our study provides a genome-wide view for the genes involving acute allograft rejection in the CD4+ T cells, and indicates that acute allograft rejection involves multiple genes in different functional categories. The genes identified from the study provide candidates for further studying the mechanisms and for monitoring, predicting and preventing acute allograft rejection.
2010-03-01 | GSE14540 | GEO
Project description:The data set contains 67 array (lymphochip cDNA array), published in N Engl J Med 2003 Jul 10;349(2):125-38. PMID: 12853585. TITLE: Molecular heterogeneity in acute renal allograft rejection identified by DNA microarray profiling. BACKGROUND: The causes and clinical course of acute rejection vary, and it is not possible to predict graft outcome reliably on the basis of available clinical, pathological, and genetic markers. We hypothesized that previously unrecognized molecular heterogeneity might underlie some of the variability in the clinical course of acute renal allograft rejection and in its response to treatment. METHODS: We used DNA microarrays in a systematic study of gene-expression patterns in biopsy samples from normal and dysfunctional renal allografts. A combination of exploratory and supervised bioinformatic methods was used to analyze these profiles. : We found consistent differences among the gene-expression patterns associated with acute rejection, nephrotoxic effects of drugs, chronic allograft nephropathy, and normal kidneys. The gene-expression patterns associated with acute rejection suggested at least three possible distinct subtypes of acute rejection that, although indistinguishable by light microscopy, were marked by differences in immune activation and cellular proliferation. Since the gene-expression patterns pointed to substantial variation in the composition of immune infiltrates, we used immunohistochemical staining to define these subtypes further. This analysis revealed a striking association between dense CD20+ B-cell infiltrates and both clinical glucocorticoid resistance (P=0.01) and graft loss (P<0.001). CONCLUSIONS: Systematic analysis of gene-expression patterns provides a window on the biology and pathogenesis of renal allograft rejection. Biopsy samples from patients with acute rejection that are indistinguishable on conventional histologic analysis reveal extensive differences in gene expression, which are associated with differences in immunologic and cellular features and clinical course. The presence of dense clusters of B cells in a biopsy sample was strongly associated with severe graft rejection, suggesting a pivotal role of infiltrating B cells in acute rejection. A disease state experiment design type is where the state of some disease such as infection, pathology, syndrome, etc is studied. Disease State: normal vs disease Keywords: disease_state_design Using regression correlation
2003-07-01 | E-GEOD-343 | biostudies-arrayexpress
Project description:Chimeric antigen receptor T-cells (CAR-T) targeting B-cell-maturating-antigen (TNRFSF17, BCMA) show unprecedented overall response rates of up to 100% in heavily pretreated relapsed-refractory Multiple Myeloma (RRMM). However, the efficiency of the treatment is hindered by the rapid emergence of tumor-intrinsic mechanisms of resistance. We herein describe a patient with RRMM and extramedullary disease (EMD) who underwent Idecabtagene vicleucel BCMA CAR-T therapy. The patient rapidly achieved very good partial response including full resolution of EMD, but aggressively relapsed 5 months after CAR T cell infusion. Single cell RNA sequencing and immunohistochemistry on the re-emerging tumor cells demonstrated loss of target expression on mRNA and protein levels, and whole genome sequencing revealed the homozygous deletion of Chr 16p1313, including the BCMA locus. Clonal heterogeneity of BCMA could be observed in 32 RRMM patients from our institution. In three of them heterozygous deletion of BCMA could be confirmed, with none of them having underwent prior anti-BCMA therapy. Thus, our report not only provides first evidence of BCMA loss as the underlying mechanism of disease relapse following BCMA targeted immunotherapy in MM. It furthermore identifies a subset of patients at risk to develop biallelic BCMA inactivation thus linking genomic instability in MM to relapse from targeted immunotherapies.
2020-12-30 | GSE143317 | GEO
Project description:The data set contains 67 array (lymphochip cDNA array), published in N Engl J Med 2003 Jul 10;349(2):125-38. PMID: 12853585. TITLE: Molecular heterogeneity in acute renal allograft rejection identified by DNA microarray profiling. BACKGROUND: The causes and clinical course of acute rejection vary, and it is not possible to predict graft outcome reliably on the basis of available clinical, pathological, and genetic markers. We hypothesized that previously unrecognized molecular heterogeneity might underlie some of the variability in the clinical course of acute renal allograft rejection and in its response to treatment. METHODS: We used DNA microarrays in a systematic study of gene-expression patterns in biopsy samples from normal and dysfunctional renal allografts. A combination of exploratory and supervised bioinformatic methods was used to analyze these profiles. : We found consistent differences among the gene-expression patterns associated with acute rejection, nephrotoxic effects of drugs, chronic allograft nephropathy, and normal kidneys. The gene-expression patterns associated with acute rejection suggested at least three possible distinct subtypes of acute rejection that, although indistinguishable by light microscopy, were marked by differences in immune activation and cellular proliferation. Since the gene-expression patterns pointed to substantial variation in the composition of immune infiltrates, we used immunohistochemical staining to define these subtypes further. This analysis revealed a striking association between dense CD20+ B-cell infiltrates and both clinical glucocorticoid resistance (P=0.01) and graft loss (P<0.001). CONCLUSIONS: Systematic analysis of gene-expression patterns provides a window on the biology and pathogenesis of renal allograft rejection. Biopsy samples from patients with acute rejection that are indistinguishable on conventional histologic analysis reveal extensive differences in gene expression, which are associated with differences in immunologic and cellular features and clinical course. The presence of dense clusters of B cells in a biopsy sample was strongly associated with severe graft rejection, suggesting a pivotal role of infiltrating B cells in acute rejection. A disease state experiment design type is where the state of some disease such as infection, pathology, syndrome, etc is studied. Disease State: normal vs disease Keywords: disease_state_design
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