Repurposing CD19-directed immunotherapies for pediatric t(8 21) acute myeloid leukemia
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ABSTRACT:
PROVIDER: PRJNA1125391 | ENA |
REPOSITORIES: ENA
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Project description:In contrast to patients with B cell precursor acute lymphoblastic leukemia (BCP-ALL), patients with acute myeloid leukemia (AML) have not yet benefited from recent advances in targeted immunotherapy. Repurposing immunotherapies that have been successfully used to target other hematological malignancies could, in case of a shared target antigen, represent a promising opportunity to expand the immunotherapeutic options for AML. Here, we evaluated the expression of CD19 in a large pediatric AML cohort, assessed the ex vivo AML killing efficacy of CD19-directed immunotherapies, and characterized the bone marrow immune microenvironment in pediatric AML, BCP-ALL, and non-leukemic controls. Out of 167 newly diagnosed de novo pediatric AML patients, 18 patients (11%) had CD19+ AML, with 61% carrying the translocation t(8;21)(q22;q22). Among CD19+ samples, we observed a continuum of CD19 expression levels on AML cells. In individuals exhibiting unimodal and high CD19 expression, the antigen was consistently present on nearly all CD34+CD38- and CD34+CD38+ subpopulations. In ex vivo AML-T cell co-cultures, blinatumomab demonstrated substantial AML killing, with an efficacy similar to BCP-ALL. In addition, CAR T cells could effectively eliminate CD19+ AML cells ex vivo. Furthermore, our immunogenomic assessment of the bone marrow immune microenvironment of newly diagnosed pediatric t(8;21) AML revealed that T- and NK cells had a less exhausted and senescent phenotype in comparison to pediatric BCP-ALL. Altogether, our study underscores the promise of CD19-directed immunotherapies for the treatment of pediatric CD19+ AML.
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Project description:Potent CD19-directed immunotherapies, such as chimeric antigen receptor T cells (CART) and blinatumomab, have drastically changed the outcome of patients with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL). However, CD19-negative relapses have emerged as a major problem that is observed in approximately 30% of treated patients. Developing approaches to preventing and treating antigen-loss escapes would therefore represent a vertical advance in the field. Here, we found that in primary patient samples, the IL-3 receptor ? chain CD123 was highly expressed on leukemia-initiating cells and CD19-negative blasts in bulk B-ALL at baseline and at relapse after CART19 administration. Using intravital imaging in an antigen-loss CD19-negative relapse xenograft model, we determined that CART123, but not CART19, recognized leukemic blasts, established protracted synapses, and eradicated CD19-negative leukemia, leading to prolonged survival. Furthermore, combining CART19 and CART123 prevented antigen-loss relapses in xenograft models. Finally, we devised a dual CAR-expressing construct that combined CD19- and CD123-mediated T cell activation and demonstrated that it provides superior in vivo activity against B-ALL compared with single-expressing CART or pooled combination CART. In conclusion, these findings indicate that targeting CD19 and CD123 on leukemic blasts represents an effective strategy for treating and preventing antigen-loss relapses occurring after CD19-directed therapies.
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2022-11-29 | GSE178919 | GEO
Project description:Immunotherapy is the revolution in cancer treatment of this last decade. Among multiple approaches able to harness the power of the immune system against cancer, T cell based immunotherapies represent one of the most successful examples. In particular, biotechnological engineering of protein structures, like the T cell receptor or the immunoglobulins, allowed the generation of synthetic peptides like chimeric antigen receptors and bispecific antibodies that are able to redirect non-tumor specific T cells to recognize and kill leukemic cells. The anti-CD19/CD3 bispecific antibody blinatumomab and anti-CD19 chimeric antigen receptor T cells (CART19) have produced deep responses in patients with relapsed and refractory B-cell acute leukemias. However, although the majority of these patients responds to anti-CD19 immunotherapy, a subset of them still relapses. Interestingly, a novel family of leukemia escape mechanisms has been described, all characterized by the apparent loss of CD19 on the surface of leukemic blasts. This extraordinary finding demonstrates the potent selective pressure of CART19/blinatumomab that drives extreme and specific escape strategies by leukemic blasts. Patients with CD19-negative relapsed leukemia have very poor prognosis and novel approaches to treat and ideally prevent antigen-loss are direly needed. In this review we discuss the incidence, mechanisms and therapeutic approaches for CD19-negative leukemia relapses occuring after CD19-directed T cell immunotherapies and present our future perspective.
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Project description:The immune response to SARS-CoV-2 varies among patients. We used proteomic analysis to study CD19+ lymphocytes, which are important for the immune response. By comparing the proteomes of CD19+ cells from healthy individuals and COVID-19 patients, we discovered proteins and signaling pathways involved in the immune response during COVID-19. This knowledge improves our understanding of immune dysregulation in COVID-19 and can help develop targeted therapies. Our research also explores the role of CD19+ lymphocytes in COVID-19 and identifies potential biomarkers. Overall, our findings contribute to understanding COVID-19 immunology and inform future research efforts.
2023-09-24 | PXD042938 | Pride
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.
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