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Placental T cells retain enhanced stemness and altered cytokine response favoring durable efficacy of CD19 CAR-T

ABSTRACT: We explored transcriptional profile of CD19 CAR-T cells generated from different starting material source (placenta vs. adult peripheral blood) with same protocol and transduced with same CAR construct

ORGANISM(S): Homo sapiens

PROVIDER: GSE231429 | GEO | 2024/04/21

REPOSITORIES: GEO

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Comparation of the anti-CD19 CAR-T and the NMN treated anti-CD19 CAR-T

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TRX1-enhanced CAR T cells retain their antitumor functions under pro-oxidative conditions

Project description:Immunotherapies with CAR-T cells achieve remarkable success, especially against B-cell malignancies. However, their activity against non-hematopoietic solid tumors is very limited. One central cause of this failure may be that a pro-oxidative tumor microenvironment can downmodulate the activation and migration of T-cells. In contrast to tumor cells, primary T cells have very low levels of antioxidants. This makes them prone to pro-oxidative effects. Oxidation-induced dysregulation of actin cytoskeletal dynamics hinders T-cell migration which allows only low tumor infiltration rates. In addition, the proliferation and the effector functions of T-cells (tumor cell killing) are disrupted. In order to strengthen human CAR-T cells against a pro-oxidative tumor microenvironment, we have increased increase their antioxidant capacity, e.g. by expressing antioxidants. We aimed to characterize the importance of antioxidant empowerment at functional level and at the molecular level. Among the antioxidant systems, thioredoxin1 (TRX1)-empowerment, allowed CAR T cells to retain their capacities for cytolytic immune synapse formation, cytokine release, proliferation, and cytotoxicity under pro-oxidative conditions. At the molecular level, gene expression analysis revealed that a pro-oxidative micromilieu caused a downmodulation of costimulatory and cytokine signals of T cells. One unique focus of this study was also to investigate global influence of reactive oxygen species on protein oxidation in T cells. Therefore, using TRX1 kinetic trapping and consequently mass spectrometry was employed to get insight into global oxidation levels in T cells. This analysis, namely redoxosome analysis, unveiled 196 oxidized proteins which were annotated to regulate several antitumor T cell functions. Taken together, our results provide evidence that TRX1 empowerment can increase CAR T cell efficacy against solid tumors.

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Project description:We have compared a low-affinity second-generation anti-CD19 CAR (CAT) with the high-affinity FMC63 CAR used in tisagenlecleucel to understand the unknown molecular mechanisms that drive different CAR T cell treatment outcomes. CAT cells are characterized by a faster antigen dissociation rate and present an enhanced in vivo expansion and anti-tumor efficacy, showing lower toxicity to patients and a long-term persistence in a Phase I clinical study. To understand this improved CAT cells behaviour, we performed a systematic in vitro characterization of the transcriptomic (RNA-seq) and protein (CyTOF) changes between the two groups. The analysis focused on T cells expressing low-affinity vs high-affinity anti-CD19 CARs following stimulation with CD19-expressing cells. Our results show that CAT potent and long-term anti-tumour responses may be sustained by the establishment of a CAR T cells self-reinforcing circuit activated through cytokines polyfunctional crosstalk. This study may inform the design of versatile CAR T cells, capable of balancing safety and efficacy.

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Human CAR T cells expressing Super2 and IL-33 retain subset identity

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Project description:Chimeric antigen receptor (CAR) therapy targeting CD19 is an effective treatment for refractory B cell malignancies, especially acute lymphoblastic leukemia (ALL). While a majority of patients will achieve a complete response following a single infusion of CD19 CAR T cells, the broad applicability of this treatment is hampered by severe cytokine release syndrome (CRS), which is characterised by fever, hypotension and respiratory insufficiency associated with elevated serum cytokines including interleukin-6 (IL-6). CRS usually occurs within days of T cell infusion at the peak of CAR T cell expansion. In ALL, it is most frequent and more severe in patients with high tumour burden CRS is often responsive to IL-6 receptor blockade, but may require intensive life support and further treatment with high dose corticosteroids to prevent potentially lethal severity. Improved therapeutic and preventive treatments require a better understanding of CRS physiopathology, which has so far remained elusive. We report here a murine model of CRS that develops within 2-3 days of CAR T cell infusion, may be lethal and is responsive to IL-6 receptor blockade. We show that its severity is mediated not by CAR T cell-derived cytokines but by IL-6, interleukin-1 (IL-1) and Nitric Oxide (NO) produced by recipient macrophages. This CRS mechanism enables novel therapeutic interventions.

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Project description: Not available

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