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Targeting CD10 on B-Cell Leukemia Using the Universal CAR T-Cell Platform (UniCAR).

ABSTRACT: Chimeric antigen receptor (CAR)-expressing T-cells are without a doubt a breakthrough therapy for hematological malignancies. Despite their success, clinical experience has revealed several challenges, which include relapse after targeting single antigens such as CD19 in the case of B-cell acute lymphoblastic leukemia (B-ALL), and the occurrence of side effects that could be severe in some cases. Therefore, it became clear that improved safety approaches, and targeting multiple antigens, should be considered to further improve CAR T-cell therapy for B-ALL. In this paper, we address both issues by investigating the use of CD10 as a therapeutic target for B-ALL with our switchable UniCAR system. The UniCAR platform is a modular platform that depends on the presence of two elements to function. These include UniCAR T-cells and the target modules (TMs), which cross-link the T-cells to their respective targets on tumor cells. The TMs function as keys that control the switchability of UniCAR T-cells. Here, we demonstrate that UniCAR T-cells, armed with anti-CD10 TM, can efficiently kill B-ALL cell lines, as well as patient-derived B-ALL blasts, thereby highlighting the exciting possibility for using CD10 as an emerging therapeutic target for B-cell malignancies.

SUBMITTER: Mitwasi N

PROVIDER: S-EPMC9105388 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Targeting CD10 on B-Cell Leukemia Using the Universal CAR T-Cell Platform (UniCAR).

Mitwasi Nicola N Arndt Claudia C Loureiro Liliana R LR Kegler Alexandra A Fasslrinner Frederick F Berndt Nicole N Bergmann Ralf R Hořejší Vaclav V Rössig Claudia C Bachmann Michael M Feldmann Anja A

International journal of molecular sciences 20220428 9

Chimeric antigen receptor (CAR)-expressing T-cells are without a doubt a breakthrough therapy for hematological malignancies. Despite their success, clinical experience has revealed several challenges, which include relapse after targeting single antigens such as CD19 in the case of B-cell acute lymphoblastic leukemia (B-ALL), and the occurrence of side effects that could be severe in some cases. Therefore, it became clear that improved safety approaches, and targeting multiple antigens, should ...[more]

PMID: 35563312

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Project description:BackgroundThe primary challenges in CD19-specific chimeric antigen receptor T-cell (CD19 CAR T) therapy for patients with refractory/relapsed B-cell acute lymphoblastic leukemia (r/r B-ALL) are non-response and relapse; it is urgent to reveal these mechanisms. Neutrophils play a critical role in the immunosuppressive tumor microenvironment (TME), which can hinder CAR T efficacy. Our previous research identified a subset of immunosuppressive neutrophils with a special phenotype (CD14-CD10-CD45-HLA-DR-SSC++, termed CD10- neuts), which suppress T cell function. Therefore, we speculate that CD10- neuts may also influence CAR T efficacy, and this study aims to clinically validate this hypothesis.MethodsWe enrolled 44 patients with r/r B-ALL undergoing CD19 CAR T therapy and 47 healthy controls (HCs). Peripheral blood samples were obtained prior to CAR T infusion to detect CD10- neuts levels by flow cytometry. Key parameters included the percentage of CD10- neuts in neutrophils (CD10- neuts/neutrophils), in all nucleated cells (CD10- neuts/nucleated cells), and the absolute count of CD10- neuts. We analyzed the correlations between these indicators and therapeutic response, relapse-free survival (RFS), overall survival (OS), and CAR T cell persistence time.ResultsCD10- neuts levels were significantly elevated in patients with r/r B-ALL compared to HCs. Additionally, non-responding patients exhibited higher CD10- neuts levels than those in remission. Specifically, CD10- neuts/neutrophils, CD10- neuts/nucleated cells, and absolute CD10- neuts count were 64.44% vs. 25.43% (p = 0.004), 28.61% vs. 9.81% (p = 0.018), and 766.1/μL vs. 152.9/μL (p = 0.04), respectively. Among these indices, only CD10- neuts/neutrophils emerged as an independent risk factor for CAR T response (OR = 19.8, p = 0.013), relapse (HR = 4.704, p = 0.004), and survival (HR = 6.417, p = 0.001). Patients with CD10- neuts/neutrophils ≥ 21.57% demonstrated significantly shorter RFS and OS compared to those with lower levels (p = 0.001; p = 0.0002). Furthermore, CD10- neuts/neutrophils were negatively correlated with the persistence time of CAR T cells.ConclusionsAs one of the key factors in the TME, abnormally elevated CD10- neuts correlate with CAR T therapy resistance. Targeting these neutrophils could enhance the effectiveness of CAR T treatment.

Dataset Information

Targeting CD10 on B-Cell Leukemia Using the Universal CAR T-Cell Platform (UniCAR).

Publications

Targeting CD10 on B-Cell Leukemia Using the Universal CAR T-Cell Platform (UniCAR).

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