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: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
Project description:NK-92 a continuously growing cell line bioengineered to express human anti-CD19 chimeric antigen receptor (CAR) CD19.TaNK recognizing CD19+ B cells represents as potential “off the shelf” therapy candidate for B cell malignancies. The goal of this study was to establish the mechanistic rationale for CD19.TaNK therapy in B-cell NHL (bNHL) and to determine the therapeutic potency in vitro against a host of bNHL cell lines, patient derived primary cell lines (including anti-CD20 antibody resistant cell lines), and in in vivo mouse models. We utilized bNHL cell lines SU-DHL10, SU-DHL4, SU-DHL2 (DLBCL), HF-1 (follicular) and Raji (Burkitt’s) and Rituximab- (RR) and obinutuzumab (OR)-resistant bNHL cell lines (SU-DHL2, SU-DHL4, SU-DHL10), and patient derived primary cells (EL-5 and KSC) were investigated the cytolytic activity of CD19.TaNK. We observed significantly increased CD19.TaNK mediated cytolytic activity at E:T ratios (1:1-10:1) via LDH release in all bNHL cell lines and CD20 resistant bHNL cells. Further, the dynamic efficacy of CD19.TaNK determined using droplet based single cell microfluidics analysis of cell interactions (1:1) between CD19.TaNK and anti-CD20 sensitive or resistant bNHL cell showed that vast majority of the cells were killed by single contact >80% (SU-DHL 4, SUD-HL 4 -OR), 40% (SU-DHL10-RR), >60% (SU-DHL10, SUD-HL-10-OR) and 40% (SU-DHL10-RR) within first 40 minutes, while the remainder were killed through events requiring multiple contacts. Thus, suggesting that CD19.TaNK indiscriminately kills both anti-CD20 sensitive and resistant cells. Global transcriptome analysis performed using flow sorted bNHL co-cultured with CD19.TaNK at 1:1 ratio for two hours, revealed conserved activation of IFNγ signaling, execution of apoptosis, ligand binding, immunoregulatory or chemokine signaling pathways in these bNHL cells. Using proximity extension assay based 92-plex cytokine panel we observed increased secretion of various cytokines, granzymes and decreased secretions of ADA, HO-1, CD5, CD28, CD70, CD244, IFN and TNF consistently with anti-CD20 sensitive and resistant cells. Altogether these results demonstrate that CD19.TaNK inflicts mechanistically conserved killing activity against different bNHL cell lines, including in anti-CD20 refractory bNHL. Finally, in SCID mice experiments we observed marked reduction in the volume of SU-DHL10 derived tumor xenografts with infusion of CD19.TaNK compared to control. Overall, we observed potent anti-lymphoma activity with CD19.TaNK involving biologically conserved mechanisms indicating that CD19.TaNK could be equally active under untreated or refractory bNHL in the clinical settings.
2018-12-01 | GSE120315 | GEO