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

Albelda, Steven M.

doi:10.1038/s41571-023-00832-4

Cited by 114 publications

(35 citation statements)

References 228 publications

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“…Recently, two main optimization directions are proposed to enhance the efficacy of CAR-T cells in solid tumors: one is to optimize traditional CAR-T construction, which aims to enhance T cell persistence and memory properties, the other is more prospective to construct CAR-T cells with shortened life span but more effector properties. 209 Multiple strategies above actually aim to shift the balance away from the disabled phenotype. CAR-T cells with naïve, stem or memory phenotypes mean they have prior ability to proliferate and persist, which propose an important consideration to optimize ex vivo CAR-T cell production.…”

Section: Conclusion and Perspectivementioning

confidence: 99%

CAR‐T‐cell products in solid tumors: Progress, challenges, and strategies

Qian,

Li,

Zhang

et al. 2024

Interdisciplinary Medicine

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T cells engineered to express chimeric antigen receptors (CARs) with specificity toward tumor cells have led to promising outcomes in patients with hematological malignancies. Nevertheless, the application of CAR‐T cell therapy in solid tumors encounters several obstacles. These include tumor heterogeneity and immune escape, T cell exhaustion and restricted infiltration into the tumors that affect the therapeutic efficacy of CAR‐T cells, as well as “on‐target, off‐tumor” toxicities that can lead to severe and even fatal adverse events. In recent years, clinical trials and new approaches of CAR‐T cell therapy for solid tumors have made certain progress. Here, we update the outcomes of related clinical trials and summarize engineered strategies aiming to improve the efficacy and therapeutic safety of CAR‐T cells based on experimental and clinical studies.

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Section: Conclusion and Perspectivementioning

confidence: 99%

CAR‐T‐cell products in solid tumors: Progress, challenges, and strategies

Qian,

Li,

Zhang

et al. 2024

Interdisciplinary Medicine

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“…Despite the fact that CAR-T cell therapy has exhibited promise in treating hematologic tumors, obstacles remain in solid tumors. [65] The accumulation of immunosuppressive metabolites in TME of solid tumor, dynamically changing metabolic ow, and the competition for nutrients from tumor cells leading to an insuf cient supply of CAR-T cells are the vital elements. Therefore, rational and effective metabolic intervention approaches are needed to improve the metabolic adaptability and anti-tumor ability of CAR-T cells in TME [Figure 2].…”

Section: Strategies For Improving the Effectiveness Of Car-t Cells By...mentioning

confidence: 99%

Targeting metabolism to improve CAR-T cells therapeutic efficacy

Liu,

Zhao,

Gao

et al. 2024

Chinese Medical Journal

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Chimeric antigen receptor T (CAR-T) cell therapy achieved advanced progress in the treatment of hematological tumors. However, the application of CAR-T cell therapy for solid tumors still faces many challenges. Competition with tumor cells for metabolic resources in an already nutrient-poor tumor microenvironment is a major contributing cause to CAR-T cell therapy’s low effectiveness. Abnormal metabolic processes are now acknowledged to shape the tumor microenvironment, which is characterized by increased interstitial fluid pressure, low pH level, hypoxia, accumulation of immunosuppressive metabolites, and mitochondrial dysfunction. These factors are important contributors to restriction of T cell proliferation, cytokine release, and suppression of tumor cell-killing ability. This review provides an overview of how different metabolites regulate T cell activity, analyzes the current dilemmas, and proposes key strategies to reestablish the CAR-T cell therapy’s effectiveness through targeting metabolism, with the aim of providing new strategies to surmount the obstacle in the way of solid tumor CAR-T cell treatment.

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“…3,4 Particularly, due to the paucity of tumor-specific antigens and the immunosuppressive tumor microenvironment, additional obstacles are posed in battle against solid tumors. 5 Innovating the design of CARs beyond that of conventional structures is necessary to address these challenges.…”

Section: ■ Introductionmentioning

confidence: 99%

“…With impressive outcomes in treating B cell malignancies, CAR T cells have sparked a revolution in cancer immunotherapy . Nevertheless, their applicability to other types of cancer is generally challenged by safety concerns, suboptimal efficacy, and complex manufacturing processes. , Particularly, due to the paucity of tumor-specific antigens and the immunosuppressive tumor microenvironment, additional obstacles are posed in battle against solid tumors . Innovating the design of CARs beyond that of conventional structures is necessary to address these challenges.…”

Section: Introductionmentioning

confidence: 99%

Aptamer-Based Nongenetic Reprogramming of CARs Enables Flexible Modulation of T Cell-Mediated Tumor Immunotherapy

Zhang,

Wu,

Zhang

et al. 2024

ACS Cent. Sci.

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Innovating the design of chimeric antigen receptors (CARs) beyond conventional structures would be necessary to address the challenges of efficacy, safety, and applicability in T cell-based cancer therapy, whereas excessive genetic modification might complicate CAR design and manufacturing, and increase gene editing risks. In this work, we used aptamers as the antigenrecognition unit to develop a nongenetic CAR engineering strategy for programming the antitumor activity and specificity of CAR T cells. Our results demonstrated that aptamer-functionalized CAR (Apt-CAR) T cells could be directly activated by recognizing target antigens on cancer cells, and then impart a cytotoxic effect for cancer elimination in vitro and in vivo. The designable antigen recognition capability of Apt-CAR T cells allows for easy modulation of their efficacy and specificity. Additionally, multiple features, e.g., tunable antigen-binding avidity and the tumor microenvironment responsiveness, could be readily integrated into Apt-CAR design without T cell re-engineering, offering a new paradigm for developing adaptable immunotherapeutics.

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

Cited by 114 publications

References 228 publications

CAR‐T‐cell products in solid tumors: Progress, challenges, and strategies

CAR‐T‐cell products in solid tumors: Progress, challenges, and strategies

Targeting metabolism to improve CAR-T cells therapeutic efficacy

Aptamer-Based Nongenetic Reprogramming of CARs Enables Flexible Modulation of T Cell-Mediated Tumor Immunotherapy

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