Generation of allogeneic CAR-NKT cells from hematopoietic stem and progenitor cells using a clinically guided culture method

Nature Biotechnology, Journal Year: 2024, Volume and Issue: unknown

Published: May 14, 2024

Abstract Cancer immunotherapy with autologous chimeric antigen receptor (CAR) T cells faces challenges in manufacturing and patient selection that could be avoided by using ‘off-the-shelf’ products, such as allogeneic CAR natural killer ( Allo CAR-NKT) cells. Previously, we reported a system for differentiating human hematopoietic stem progenitor into CAR-NKT cells, but the use of three-dimensional culture xenogeneic feeders precluded its clinical application. Here describe clinically guided method to differentiate expand IL-15-enhanced high yield purity. We generated targeting seven cancers and, multiple myeloma model, demonstrated their antitumor efficacy, expansion persistence. The also selectively depleted immunosuppressive tumor microenviroment antagonized immune evasion via triple CAR, TCR NK receptors. They exhibited stable hypoimmunogenic phenotype associated epigenetic signaling regulation did not induce detectable graft versus host disease or cytokine release syndrome. These properties support potential translation.

Language: Английский

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Engineering allorejection-resistant CAR-NKT cells from hematopoietic stem cells for off-the-shelf cancer immunotherapy

Molecular Therapy, Journal Year: 2024, Volume and Issue: 32(6), P. 1849 - 1874

Published: April 6, 2024

The clinical potential of current FDA-approved chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy is encumbered by its autologous nature, which presents notable challenges related to manufacturing complexities, heightened costs, and limitations in patient selection. Therefore, there a growing demand for off-the-shelf universal therapies. In this study, we have generated CAR-engineered NKT (

Language: Английский

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Allogeneic CD33-directed CAR-NKT cells for the treatment of bone marrow-resident myeloid malignancies

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 1, 2025

Abstract Chimeric antigen receptor (CAR)-engineered T cell therapy holds promise for treating myeloid malignancies, but challenges remain in bone marrow (BM) infiltration and targeting BM-resident malignant cells. Current autologous CAR-T therapies also face manufacturing patient selection issues, underscoring the need off-the-shelf products. In this study, we characterize primary samples identify a unique therapeutic opportunity CAR-engineered invariant natural killer (CAR-NKT) Using stem gene engineering clinically guided culture method, generate allogeneic CD33-directed CAR-NKT cells with high yield, purity, robustness. preclinical mouse models, exhibit strong BM homing effectively target blast cells, including CD33-low/negative leukemia progenitor Furthermore, synergize hypomethylating agents, enhancing tumor-killing efficacy. These show minimal off-tumor toxicity, reduced graft-versus-host disease cytokine release syndrome risks, resistance to allorejection, highlighting their substantial potential malignancies.

Language: Английский

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Recent updates on allogeneic CAR-T cells in hematological malignancies

Cancer Cell International, Journal Year: 2024, Volume and Issue: 24(1)

Published: Sept. 3, 2024

CAR-T cell therapy is known as an effective in patients with hematological malignancies. Since 2017, several autologous (auto-CAR-T) drugs have been approved by the US Food and Drug Administration (FDA) for treatment of some kinds relapsed/refractory However, fail to respond these due high manufacturing time, batch-to-batch variation, poor quality insufficient quantity primary T cells, their expansion function. cells prepared from allogeneic sources (allo-CAR-Ts) can be alternative option overcome obstacles. Recently, allo-CAR-Ts entered into early clinical trials. Despite promising preclinical results, there are two main barriers, including graft-versus-host disease (GvHD) allo-rejection that may decline safety efficacy clinic. The successful development products depends on starter source, gene editing method, ability escape immune rejection prevent GvHD. Here, we summarize technologies potential various developing highlight advantages We also describe data focusing allo-CAR-T blood malignancies discuss challenges future perspectives therapeutic applications.

Language: Английский

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Generating allogeneic CAR-NKT cells for off-the-shelf cancer immunotherapy with genetically engineered HSP cells and feeder-free differentiation culture

Nature Protocols, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 17, 2025

Language: Английский

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The clinical landscape of CAR-engineered unconventional T cells

Trends in cancer, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Unconventional T cells, such as invariant natural killer (iNKT), γδ T, and mucosal-associated (MAIT) play a pivotal role in bridging innate adaptive immunity. Their capacity for rapid tumor targeting effective modulation of the microenvironment (TME) makes them promising candidates cancer immunotherapy. Advances chimeric antigen receptor (CAR) engineering have further highlighted their therapeutic potential, particularly treating challenging cancers. Notably, these cells exhibit favorable safety profiles, enhancing viability off-the-shelf options. We provide comprehensive analysis clinical applications CAR-engineered unconventional focusing on genetic modifications, manufacturing processes, preconditioning regimens, dosing strategies. discuss successful examples from recent trials explore future directions utilizing therapy beyond.

Language: Английский

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Non-viral approaches in CAR-NK cell engineering: connecting natural killer cell biology and gene delivery

Journal of Nanobiotechnology, Journal Year: 2024, Volume and Issue: 22(1)

Published: Sept. 10, 2024

Language: Английский

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Multi-omics analysis reveals a feedback loop amplifying immune responses in acute graft-versus-host disease due to imbalanced gut microbiota and bile acid metabolism

Journal of Translational Medicine, Journal Year: 2024, Volume and Issue: 22(1)

Published: Aug. 7, 2024

Acute graft-versus-host disease (aGVHD) is primarily driven by allogeneic donor T cells associated with an altered composition of the host gut microbiome and its metabolites. The severity aGVHD after hematopoietic stem cell transplantation (allo-HSCT) not solely determined characteristics; however, underlying mechanisms remain unclear. Using single-cell RNA sequencing, we decoded immune atlas 12 patients who underwent allo-HSCT: six non-aGVHD. We performed a fecal microbiota (16SrRNA sequencing) analysis to investigate bacterial 82 patients: 30 52 Fecal samples from these were analyzed for bile acid metabolism. Through multi-omic analysis, identified feedback loop involving "immune cell-gut microbes-bile metabolites" contributing heightened responses in aGVHD. dysbiosis disruption metabolism contributed exaggerated interleukin-1 mediated response. Our findings suggest that resistin defensins are crucial mitigating against Therefore, comprehensive incorporating cells, microbes, metabolites was developed this study used propose novel, non-immunosuppressive approaches prevent

Language: Английский

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Early intervention with oral mucosal barrier Protective agents in chronic oral graft-versus-host disease: a retrospective cohort study

BMC Oral Health, Journal Year: 2024, Volume and Issue: 24(1)

Published: Aug. 17, 2024

Preventing the progression of chronic oral graft-versus-host disease (cGVHD) is essential for maintaining health, improving quality life, minimizing functional impairment, reducing systemic complications, and addressing treatment challenges.

Language: Английский

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The Role of Innate T Cells in Cancer

Springer eBooks, Journal Year: 2023, Volume and Issue: unknown, P. 1 - 18

Published: Nov. 11, 2023

Language: Английский

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