Sequential Antigen-loss and Branching Evolution in Lymphoma after Anti-CD19 and Anti-CD20 Targeted T Cell Engaging Immunotherapy
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ABSTRACT:
PROVIDER: EGAS00001007561 | EGA |
REPOSITORIES: EGA
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Project description:<p>Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (r/r) large B-cell lymphoma (LBCL) results in durable response in only a subset of patients. MYC overexpression in LBCL tumors is associated with poor response to treatment. We tested whether a MYC-driven polyamine signature, as a liquid biopsy, is predictive of response to anti-CD19 CAR-T therapy in patients with r/r LBCL. Elevated plasma acetylated polyamines were associated with non-durable response. Concordantly, increased expression of spermidine synthase, a key enzyme which regulates levels of acetylated spermidine, was prognostic for survival in r/r LBCL. A broad metabolite screen identified additional markers which resulted in a 6-marker panel (6MetP) consisting of acetylspermidine, diacetylspermidine and lysophospholipids which was validated in an independent set from another institution as predictive of non-durable response to CAR T therapy. A polyamine centric metabolomics liquid biopsy panel has predictive value for response to CAR-T therapy in r/r LBCL. </p>
2022-10-31 | MTBLS5381 | MetaboLights
Project description:A significant challenge for chimeric antigen receptor (CAR) T cell therapy against glioblastoma (GBM) is its immunosuppressive tumor microenvironment (TME), which is densely populated and supported by protumoral glioma-associated microglia and macrophages (GAMs). Targeting CD47, a don't-eat-me signal overexpressed by tumor cells, disrupts the CD47-SIRPalpha axis and induces GAM phagocytic function. However, antibody-mediated CD47 blockade monotherapy is associated with toxicity and low bioavailability in solid tumors. To overcome these limitations, we combined local CAR T cell therapy with paracrine GAM modulation to effectively eliminate GBM. To this end, we engineered a new CAR T cell against epidermal growth factor receptor variant III (EGFRvIII) that constitutively secretes a signal regulatory protein gamma (SIRPgamma)-related protein (SGRP) with high affinity to CD47. Anti-EGFRvIII-SGRP CAR T cells eliminated EGFRvIII+ GBM in a dose-dependent manner in vitro and eradicated orthotopically xenografted EGFRvIII-mosaic GBM by locoregional application in vivo. This resulted in significant tumor-free long-term survival, followed by partial tumor control upon tumor re-challenge. Combining anti-CD47 antibodies with anti-EGFRvIII CAR T cells failed to achieve a similar therapeutic effect, underscoring the importance of sustained paracrine GAM modulation. Multidimensional brain immunofluorescence microscopy and in-depth spectral flow cytometry on GBM-xenografted brains showed that anti-EGFRvIII-SGRP CAR T cells accelerated GBM clearance, increased CD68+ cell trafficking to tumor scar sites and promoted GAM-mediated tumor cell uptake. In a peripheral lymphoma mouse xenograft model, anti-CD19-SGRP CAR T cells had superior efficacy to conventional anti-CD19 CAR T cells. Validation on human GBM explants revealed that anti-EGFRvIII-SGRP CAR T cells had a similar tumor-killing capacity to anti-EGFRvIII CAR monotherapy but showed a slight improvement in the maintenance of tumor-infiltrated CD14+ cells. Thus, local anti-EGFRvIII-SGRP CAR T cell therapy combines the potent antitumor effect of engineered T cells with the modulation of the surrounding innate immune TME. This results in the additive elimination of bystander EGFRvIII- tumor cells in a manner that overcomes the main mechanisms of CAR T cell therapy resistance, including tumor innate immune suppression and antigen escape.
2024-07-19 | MSV000095386 | MassIVE
Project description:Recent improvements in relapse/refractory B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) outcome can be attributed, in part, to the emergence of CD19-directed immune-based therapies including chimeric antigen receptor (CAR)-T cell therapy and bi-specific T cell engager (BiTE) therapy. Longitudinal BCP-ALL studies have highlighted individual cases of progressive surface CD19 antigen reduction associated with disease persistence following CAR-T infusion. CD19 genomic deletions and mRNA alternative splicing have been previously shown to confer CAR-T and BiTE resistance, however gene regulatory programs that modulate BCP-ALL CD19 surface antigen abundance remains poorly understood. To address this, we performed genome-wide CRISPR/Cas9 screening to identify positive and negative regulators of surface CD19 abundance in human BCP-ALL as compared to mature B cell neoplasms, chronic lymphocytic leukemia and B cell lymphoma. Here, we show DNA binding protein, ZNF143, occupies the CD19 promoter and transcriptionally regulates CD19 mRNA expression in human B-cell malignancies. Conversely, we show that RNA-binding protein, NUDT21, limits surface CD19 abundance on BCP-ALL. NUDT21 acts to regulate CD19 3’ UTR length and CD19 mRNA stability. NUDT21 mRNA displays high concordance with CD19 mRNA expression in primary healthy and transformed human B cell progenitors. Using primary BCP-ALL patient single cell data, we show that reduction of CD19 mRNA expression following CAR-T therapy coincides with increased NUDT21 mRNA expression. Importantly, NUDT21 ablation sensitizes BCP-ALL to BiTE and CD19 CAR-T killing ex vivo. These findings reveal previously unknown modulators of CD19 antigen abundance that can be applied to therapeutically enhance or determine resistance to CD19-based therapies in B-cell leukemias.
2022-07-27 | GSE190841 | GEO
Project description:Recent improvements in relapse/refractory B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) outcome can be attributed, in part, to the emergence of CD19-directed immune-based therapies including chimeric antigen receptor (CAR)-T cell therapy and bi-specific T cell engager (BiTE) therapy. Longitudinal BCP-ALL studies have highlighted individual cases of progressive surface CD19 antigen reduction associated with disease persistence following CAR-T infusion. CD19 genomic deletions and mRNA alternative splicing have been previously shown to confer CAR-T and BiTE resistance, however gene regulatory programs that modulate BCP-ALL CD19 surface antigen abundance remains poorly understood. To address this, we performed genome-wide CRISPR/Cas9 screening to identify positive and negative regulators of surface CD19 abundance in human BCP-ALL as compared to mature B cell neoplasms, chronic lymphocytic leukemia and B cell lymphoma. Here, we show DNA binding protein, ZNF143, occupies the CD19 promoter and transcriptionally regulates CD19 mRNA expression in human B-cell malignancies. Conversely, we show that RNA-binding protein, NUDT21, limits surface CD19 abundance on BCP-ALL. NUDT21 acts to regulate CD19 3’ UTR length and CD19 mRNA stability. NUDT21 mRNA displays high concordance with CD19 mRNA expression in primary healthy and transformed human B cell progenitors. Using primary BCP-ALL patient single cell data, we show that reduction of CD19 mRNA expression following CAR-T therapy coincides with increased NUDT21 mRNA expression. Importantly, NUDT21 ablation sensitizes BCP-ALL to BiTE and CD19 CAR-T killing ex vivo. These findings reveal previously unknown modulators of CD19 antigen abundance that can be applied to therapeutically enhance or determine resistance to CD19-based therapies in B-cell leukemias.
2022-07-27 | GSE191007 | GEO
Project description:Recent improvements in relapse/refractory B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) outcome can be attributed, in part, to the emergence of CD19-directed immune-based therapies including chimeric antigen receptor (CAR)-T cell therapy and bi-specific T cell engager (BiTE) therapy. Longitudinal BCP-ALL studies have highlighted individual cases of progressive surface CD19 antigen reduction associated with disease persistence following CAR-T infusion. CD19 genomic deletions and mRNA alternative splicing have been previously shown to confer CAR-T and BiTE resistance, however gene regulatory programs that modulate BCP-ALL CD19 surface antigen abundance remains poorly understood. To address this, we performed genome-wide CRISPR/Cas9 screening to identify positive and negative regulators of surface CD19 abundance in human BCP-ALL as compared to mature B cell neoplasms, chronic lymphocytic leukemia and B cell lymphoma. Here, we show DNA binding protein, ZNF143, occupies the CD19 promoter and transcriptionally regulates CD19 mRNA expression in human B-cell malignancies. Conversely, we show that RNA-binding protein, NUDT21, limits surface CD19 abundance on BCP-ALL. NUDT21 acts to regulate CD19 3’ UTR length and CD19 mRNA stability. NUDT21 mRNA displays high concordance with CD19 mRNA expression in primary healthy and transformed human B cell progenitors. Using primary BCP-ALL patient single cell data, we show that reduction of CD19 mRNA expression following CAR-T therapy coincides with increased NUDT21 mRNA expression. Importantly, NUDT21 ablation sensitizes BCP-ALL to BiTE and CD19 CAR-T killing ex vivo. These findings reveal previously unknown modulators of CD19 antigen abundance that can be applied to therapeutically enhance or determine resistance to CD19-based therapies in B-cell leukemias.
2022-07-27 | GSE190843 | GEO
Project description:Recent improvements in relapse/refractory B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) outcome can be attributed, in part, to the emergence of CD19-directed immune-based therapies including chimeric antigen receptor (CAR)-T cell therapy and bi-specific T cell engager (BiTE) therapy. Longitudinal BCP-ALL studies have highlighted individual cases of progressive surface CD19 antigen reduction associated with disease persistence following CAR-T infusion. CD19 genomic deletions and mRNA alternative splicing have been previously shown to confer CAR-T and BiTE resistance, however gene regulatory programs that modulate BCP-ALL CD19 surface antigen abundance remains poorly understood. To address this, we performed genome-wide CRISPR/Cas9 screening to identify positive and negative regulators of surface CD19 abundance in human BCP-ALL as compared to mature B cell neoplasms, chronic lymphocytic leukemia and B cell lymphoma. Here, we show DNA binding protein, ZNF143, occupies the CD19 promoter and transcriptionally regulates CD19 mRNA expression in human B-cell malignancies. Conversely, we show that RNA-binding protein, NUDT21, limits surface CD19 abundance on BCP-ALL. NUDT21 acts to regulate CD19 3’ UTR length and CD19 mRNA stability. NUDT21 mRNA displays high concordance with CD19 mRNA expression in primary healthy and transformed human B cell progenitors. Using primary BCP-ALL patient single cell data, we show that reduction of CD19 mRNA expression following CAR-T therapy coincides with increased NUDT21 mRNA expression. Importantly, NUDT21 ablation sensitizes BCP-ALL to BiTE and CD19 CAR-T killing ex vivo. These findings reveal previously unknown modulators of CD19 antigen abundance that can be applied to therapeutically enhance or determine resistance to CD19-based therapies in B-cell leukemias.
2022-07-27 | GSE190842 | GEO
Project description:Adoptive cell therapy, a subset of cancer immunotherapy, is collection of therapeutic approaches which aim to redirect the immune system by reprogramming patient T-cells to target antigenic molecules differentially and specifically expressed in certain cancers. One promising immunotherapy technique is CAR T-cell therapy, where cancer cells are targeted through the expression a chimeric antigen receptor (CAR), a synthetic trans- membrane receptor that functionally compensates for the T-cell receptor (TCR) but targets a tumor associated antigen on the cancer cell surface. While CAR T-cell therapy is promising with two clinically approved second-generation CARs (Kymriah and Yescarta), few studies have investigated the mechanism of signal propagation in T-cells and no studies have investigated the potential signaling response in the target cells. To gain further insight to CAR-based signaling, we stimulated third generation CD19 CAR-expressing Jurkat T-cells by co-culture with SILAC labeled CD19HI Raji B-cells and used two phosphoenrichment strategies coupled with liquid chromatography-tandem mass spec- trometry (LC-MS/MS) to detect and analyze global phosphorylation changes in both cell populations. Analysis of the phosphopeptides originating from the CD19-CAR T cells revealed an increase in many phosphorylation events necessary for canonical TCR signaling. We also observed for the first time a significant decrease in B-cell receptor- related phosphopeptide abundance in CD19HI Raji B-cells after co-culture with CD19-targetted CAR T-cells.
2022-01-28 | PXD028109 | Pride
Project description:The clinical success of chimeric antigen receptor (CAR) T-cell therapy for CD19+ B-cell malignancies may come at the expense of acute and chronic morbidities. Some patients suffer from significant, acute toxicities and those with persistent CAR T-cells require immunoglobulin therapy due to CAR-induced B-cell aplasia. Life-threatening effects include cytokine release syndrome, the exact etiology of which is unclear. To elucidate the underlying mechanisms of CAR-induced toxicities, we developed a mouse model in which human CD19 (hCD19)-specific mouse CAR T-cells were adoptively transferred into mice whose normal B-cells express a hCD19 transgene at hemizygous levels. In contrast to homozygous mice, hemizygous mice have higher B cell frequencies, providing a greater target antigen load to drive CAR-T cell activation. Hemizygous mice given a lethal dose of hCD19 transgene-expressing lymphoma cells and treated with CAR-T cells had undetectable levels of tumor. However, recipients experienced acute B-cell aplasia, morbidities and mortality in an antigen- and dose-dependent manner. IL-6, INF-g, and inflammatory pathway transcripts were enriched in affected tissues. As in patients, antibody-mediated neutralization of IL-6 blunted toxicity. This new model will prove useful in testing strategies designed to improve CD19-specific CAR T-cell therapy by reducing acute toxicities and reversing B-cell aplasia.
2018-02-01 | GSE102618 | GEO
Project description:The clinical success of chimeric antigen receptor (CAR) T-cell therapy for CD19+ B-cell malignancies may come at the expense of acute and chronic morbidities. Some patients suffer from significant, acute toxicities and those with persistent CAR T-cells require immunoglobulin therapy due to CAR-induced B-cell aplasia. Life-threatening effects include cytokine release syndrome, the exact etiology of which is unclear. To elucidate the underlying mechanisms of CAR-induced toxicities, we developed a mouse model in which human CD19 (hCD19)-specific mouse CAR T-cells were adoptively transferred into mice whose normal B-cells express a hCD19 transgene at hemizygous levels. In contrast to homozygous mice, hemizygous mice have higher B cell frequencies, providing a greater target antigen load to drive CAR-T cell activation. Hemizygous mice given a lethal dose of hCD19 transgene-expressing lymphoma cells and treated with CAR-T cells had undetectable levels of tumor. However, recipients experienced acute B-cell aplasia, morbidities and mortality in an antigen- and dose-dependent manner. IL-6, INF-g, and inflammatory pathway transcripts were enriched in affected tissues. As in patients, antibody-mediated neutralization of IL-6 blunted toxicity. This new model will prove useful in testing strategies designed to improve CD19-specific CAR T-cell therapy by reducing acute toxicities and reversing B-cell aplasia.
2018-02-01 | GSE102617 | GEO
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