A guide to CAR T cell therapies: development, current status and future prospects.

Emerging CAR-T Cell Therapies for T Cell Malignancies: Innovations, Challenges, and Future Directions

Continued efforts to identify highly specific target antigens, optimize manufacturing processes, enhance safety, and integrate CAR-T therapy with complementary immunotherapeutic approaches are expected to improve clinical outcomes and broaden the application of CAR-T therapy to T-cell malignancies and potentially other solid and hematologic cancers.

In vivo CAR‑T therapy: recent progress and future directions

Beyond Conventional CARs: Expanding the Targetable Antigen Landscape in CAR-T Cell Therapy.

This review aims to provide a comprehensive overview of recent advances in the design of innovative CAR architectures to expand the targetable antigen landscape and discusses innovative CARs in four main categories.

Expanding the Horizon of CAR-T Cell Therapy: Present Obstacles and New Strategies for Future CARs in Solid Tumors.

Chimeric antigen receptor (CAR)-T cells are synthetic receptors used for the recognition of specific antigens expressed by reprogrammed T cells for targeting tumors. CAR-T cell therapy has gained remarkable clinical success for the treatment of hematological malignancies such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), lymphoplasmacytic lymphoma (LPL), and primary intraocular lymphoma (PIL). The increasing number of preclinical investigations and clinical trials is focusing on extending CAR-T cell therapy to solid tumors due to its remarkable success in leukemia and lymphoma cancers. However, some limitations of CAR-T therapy still exist, including a lack of targetable antigen diversity, heterogeneous antigen expression, insufficient T-cell trafficking efficiency, and an immunosuppressive tumor microenvironment. This review explores the role of CAR-T cell therapy, current challenges, and emerging solutions for solid tumor malignancies. To overcome the existing limitations of CAR-T cell therapy, innovative strategies, including the optimization of novel CAR vectors with checkpoint inhibitors, have been designed to enhance the antitumor activity of CAR-T cells against solid tumors. It also explores the design of novel CAR-T cells and strategies for improving antitumor activity against solid tumors. Among the emerging strategies, universal CARs and combination approaches with checkpoint inhibitors are especially promising for extending CAR-T therapy to solid tumors.

In-vivo CAR-T Cell Engineering: A Narrative Review of Emerging Delivery Strategies and Their Potential Future Impact on Accessibility

Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a groundbreaking advancement in cancer immunotherapy, progressively improving over decades and producing remarkable clinical outcomes. This review examines the evolution of CAR-T cell therapy by comparing ex vivo and newer in-vivo approaches, evaluating the four primary delivery vehicles used for in-vivo CAR-T therapy, and discussing their implications for safety, scalability, accessibility and future development. Although ex vivo CAR-T therapy has demonstrated substantial clinical success, its complex manufacturing process, high cost, prolonged production time, and reliance on specialized facilities limit patient access worldwide. In contrast, in-vivo CAR-T therapy genetically reprograms T cells directly within the body, eliminating external manipulation of T cells and thus many of the logistical barriers associated with ex vivo manufacturing. Four primary delivery vehicles have shown immense progress within-vivo CAR-T cell therapy: lentiviral vectors, lipid nanoparticles, polymeric nanoparticles, and virus-like particles. Each delivery platform offers distinct advantages and limitations in terms of efficacy, safety, and scalability. Most evidence for in-vivo CAR-T therapy to date comes from preclinical and early-phase studies; if these approaches continue to mature, they may offer a more scalable, cost-effective, and accessible alternative to traditional ex vivo CAR-T therapy, though this remains a projected rather than demonstrated benefit.

In vivo CAR T cells on the highway: a roadmap for the next decade.

INTRODUCTION Chimeric antigen receptor (CAR) T cell therapy has shown efficacy in the treatment of hematological malignancies. However, the application to a broader patient population is still limited by the complex logistics in coordinating the lymphodepleting chemotherapy and the labor-, time-, and cost-intensive ex vivo manufacturing of patients' CAR T cells in specialized centers. By combining recent advances in lipid nanotechnology, RNA chemistry, and viral particle targeting, engineering CAR T cells in the patient's blood stream is becoming an emerging option that may overcome current limitations. Advanced pre-clinical and early clinical studies support this approach by demonstrating successful engineering of CAR T cells in vivo and producing some anti-tumor responses in clinical trials. AREAS COVERED We review delivery strategies using viral and non-viral vectors, summarize the translation into clinical application, and outline strategies for optimization. We further discuss current challenges with respect to targeting specificity, genomic safety, pharmacokinetics, host immune responses, and regulatory oversight. EXPERT OPINION Although still in its infancy, in vivo genetic engineering shows promise for CAR T cell therapy in a wide range of cancer patients. It also has the potential to reprogram patients' immunity in autoimmunity, chronic infections, and regenerative medicine.