CAR immune cells: design principles, resistance and the next generation

Nature, Journal Year: 2023, Volume and Issue: 614(7949), P. 635 - 648

Published: Feb. 22, 2023

Language: Английский

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CAR-cell therapy in the era of solid tumor treatment: current challenges and emerging therapeutic advances

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: Jan. 30, 2023

In the last decade, Chimeric Antigen Receptor (CAR)-T cell therapy has emerged as a promising immunotherapeutic approach to fight cancers. This consists of genetically engineered immune cells expressing surface receptor, called CAR, that specifically targets antigens expressed on tumor cells. hematological malignancies like leukemias, myeloma, and non-Hodgkin B-cell lymphomas, adoptive CAR-T shown efficacy in treating chemotherapy refractory patients. However, value this remains inconclusive context solid tumors is restrained by several obstacles including limited trafficking infiltration, presence an immunosuppressive microenvironment, well adverse events associated with such therapy. Recently, CAR-Natural Killer (CAR-NK) CAR-macrophages (CAR-M) were introduced complement/alternative for tumors. CAR-NK could be favorable substitute since they do not require HLA compatibility have toxicity. Additionally, might generated large scale from sources which would suggest them off-the-shelf product. CAR-M immunotherapy its capabilities phagocytosis, tumor-antigen presentation, broad currently being investigated. Here, we discuss emerging role CAR-T, CAR-NK, We also highlight advantages drawbacks compared Finally, prospective solutions potential combination therapies enhance CAR-cells immunotherapy.

Language: Английский

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Overcoming on-target, off-tumour toxicity of CAR T cell therapy for solid tumours

Nature Reviews Clinical Oncology, Journal Year: 2022, Volume and Issue: 20(1), P. 49 - 62

Published: Nov. 23, 2022

Language: Английский

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Cancer neuroscience: State of the field, emerging directions

Cell, Journal Year: 2023, Volume and Issue: 186(8), P. 1689 - 1707

Published: April 1, 2023

The nervous system governs both ontogeny and oncology. Regulating organogenesis during development, maintaining homeostasis, promoting plasticity throughout life, the plays parallel roles in regulation of cancers. Foundational discoveries have elucidated direct paracrine electrochemical communication between neurons cancer cells, as well indirect interactions through neural effects on immune stromal cells tumor microenvironment a wide range malignancies. Nervous system-cancer can regulate oncogenesis, growth, invasion metastatic spread, treatment resistance, stimulation tumor-promoting inflammation, impairment anti-cancer immunity. Progress neuroscience may create an important new pillar therapy.

Language: Английский

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From bench to bedside: the history and progress of CAR T cell therapy

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: May 15, 2023

Chimeric antigen receptor (CAR) T cell therapy represents a major breakthrough in cancer care since the approval of tisagenlecleucel by Food and Drug Administration 2017 for treatment pediatric young adult patients with relapsed or refractory acute lymphocytic leukemia. As April 2023, six CAR therapies have been approved, demonstrating unprecedented efficacy B-cell malignancies multiple myeloma. However, adverse events such as cytokine release syndrome immune effector cell-associated neurotoxicity pose significant challenges to therapy. The severity these correlates pretreatment tumor burden, where higher burden results more severe consequences. This observation is supported application CD19-targeted autoimmune diseases including systemic lupus erythematosus antisynthetase syndrome. These indicate that initiating early at low using debulking strategy prior infusion may reduce events. In addition, expensive has limited effectiveness against solid tumors. this article, we review critical steps led groundbreaking explore ongoing efforts overcome challenges. With promise effective safer development, are optimistic broader range will benefit from revolutionary foreseeable future.

Language: Английский

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CAR T cell therapy for patients with solid tumours: key lessons to learn and unlearn

Nature Reviews Clinical Oncology, Journal Year: 2023, Volume and Issue: 21(1), P. 47 - 66

Published: Oct. 30, 2023

Language: Английский

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Intraventricular B7-H3 CAR T Cells for Diffuse Intrinsic Pontine Glioma: Preliminary First-in-Human Bioactivity and Safety

Cancer Discovery, Journal Year: 2022, Volume and Issue: 13(1), P. 114 - 131

Published: Oct. 19, 2022

Diffuse intrinsic pontine glioma (DIPG) remains a fatal brainstem tumor demanding innovative therapies. As B7-H3 (CD276) is expressed on central nervous system (CNS) tumors, we designed B7-H3-specific chimeric antigen receptor (CAR) T cells, confirmed their preclinical efficacy, and opened BrainChild-03 (NCT04185038), first-in-human phase I trial administering repeated locoregional CAR cells to children with recurrent/refractory CNS tumors DIPG. Here, report the results of first three evaluable patients DIPG (including two who enrolled after progression), received 40 infusions no dose-limiting toxicities. One patient had sustained clinical radiographic improvement through 12 months study. Patients exhibited correlative evidence local immune activation persistent cerebrospinal fluid (CSF) cells. Targeted mass spectrometry CSF biospecimens revealed modulation critical analytes (CD14, CD163, CSF-1, CXCL13, VCAM-1). Our data suggest feasibility intracranial T-cell dosing that delivery may induce activation. This repeatedly dosed for includes preliminary tolerability, detection in CSF, cytokine elevations supporting activation, serial from both serum CSF. article highlighted In Issue feature, p. 1.

Language: Английский

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Intraventricular CARv3-TEAM-E T Cells in Recurrent Glioblastoma

New England Journal of Medicine, Journal Year: 2024, Volume and Issue: 390(14), P. 1290 - 1298

Published: March 13, 2024

SummaryIn this first-in-human, investigator-initiated, open-label study, three participants with recurrent glioblastoma were treated CARv3-TEAM-E T cells, which are chimeric antigen receptor (CAR) cells engineered to target the epidermal growth factor (EGFR) variant III tumor-specific antigen, as well wild-type EGFR protein, through secretion of a T-cell–engaging antibody molecule (TEAM). Treatment did not result in adverse events greater than grade 3 or dose-limiting toxic effects. Radiographic tumor regression was dramatic and rapid, occurring within days after receipt single intraventricular infusion, but responses transient two participants. (Funded by Gateway for Cancer Research others; INCIPIENT ClinicalTrials.gov number, NCT05660369.)

Language: Английский

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Emerging phagocytosis checkpoints in cancer immunotherapy

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: March 7, 2023

Abstract Cancer immunotherapy, mainly including immune checkpoints-targeted therapy and the adoptive transfer of engineered cells, has revolutionized oncology landscape as it utilizes patients’ own systems in combating cancer cells. cells escape surveillance by hijacking corresponding inhibitory pathways via overexpressing checkpoint genes. Phagocytosis checkpoints, such CD47, CD24, MHC-I, PD-L1, STC-1 GD2, have emerged essential checkpoints for immunotherapy functioning “don’t eat me” signals or interacting with “eat to suppress responses. link innate immunity adaptive immunotherapy. Genetic ablation these phagocytosis well blockade their signaling pathways, robustly augments reduces tumor size. Among all CD47 is most thoroughly studied a rising star among targets treatment. CD47-targeting antibodies inhibitors been investigated various preclinical clinical trials. However, anemia thrombocytopenia appear be formidable challenges since ubiquitously expressed on erythrocytes. Here, we review reported discussing mechanisms functions highlight progress targeting discuss potential solutions smooth way combination immunotherapeutic strategies that involve both

Language: Английский

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Co-opting signalling molecules enables logic-gated control of CAR T cells

Nature, Journal Year: 2023, Volume and Issue: 615(7952), P. 507 - 516

Published: March 8, 2023

Language: Английский

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