Tracking therapeutic T cells in vivo.

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

The landscape of genetic medicines for in vivo T cell reprogramming.

Key challenges related to the biodistribution, activation, and persistence of modified T cells are highlighted, with an emphasis on the potential of these strategies for treating not only blood cancers but also solid tumors, autoimmune diseases, and beyond.

Engineering T cells in vivo to express a synthetic cytokine receptor enables preferential expansion and enrichment of anti-CD22 CAR T cells.

Ex vivo-manufactured chimeric antigen receptor (CAR) T cells targeting CD19 have transformed treatment strategies for patients with B cell malignancies and shown promising results in autoimmune disease. Yet despite their success, significant barriers remain that impede patient access to these therapies, including their complex manufacturing and the need for lymphodepleting chemotherapy. Moreover, many patients who receive ex vivo-manufactured CD19 CAR T cells do not achieve durable responses, suggesting that the expansion and persistence of CAR T cells may need improvement, and/or that strategies targeting alternative antigens may be needed for patients who are refractory to or relapse following treatment with CD19-directed therapies. Umoja is developing a surface-engineered lentiviral vector (LVV) platform capable of generating CAR T cells in vivo without lymphodepletion. UB-VV400 delivers a payload comprised of a fully human anti-CD22 CAR and the rapamycin-activated cytokine receptor (RACR), which enable preferential expansion and enrichment of CAR T cells in response to rapamycin. Here, we describe preclinical studies demonstrating that UB-VV400 generates anti-CD22 CAR T cells that kill CD22-expressing B cells and tumor cells in vitro and in vivo, and that engagement of RACR results in the selective expansion and enrichment of CAR T cells in vivo leading to complete tumor clearance and B cell depletion.

Recent advances in molecular mechanisms to improve the efficacy of CAR-T cell therapy for viral diseases, cancer, and autoimmune diseases

Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of hematological malignancies, yet its broader application to solid tumors, chronic viral infections, and autoimmune diseases remains constrained by antigen heterogeneity, immunosuppressive tissue microenvironments, T-cell exhaustion, limited persistence, and treatment-associated toxicities. These challenges have shifted the field from optimizing individual receptor constructs toward engineering CAR-T cells as programmable immune systems capable of adapting to diverse disease contexts. This review synthesizes recent advances in molecular engineering strategies that enhance CAR-T cell function beyond conventional receptor design. We discuss how receptor engineering, genome editing, transcriptional and epigenetic regulation, metabolic reprogramming, synthetic gene circuits, and safety-control platforms collectively reshape CAR-T cell fate, persistence, and therapeutic efficacy. Rather than functioning independently, these engineering strategies are increasingly integrated to generate context-specific cellular therapies capable of adapting to diverse disease environments, including cancer, autoimmune diseases, and chronic viral infections. We also highlight the potential for translation into clinical practice or clinical translation and discuss the major challenges associated with clinical implementation. Next-generation CAR-T therapies will increasingly integrate molecular engineering strategies or will rely on molecular engineering strategies to integrate antigen recognition, cellular fitness, immune regulation, and longevity rather than simply maximizing cytotoxic activity. Recent advances in programmable cellular engineering coupled with rigorous clinical evaluation as well as scalable manufacturing technologies or scalable manufacturing platforms in the treatment of other diseases beyond oncology will facilitate the development of safer, more durable, and broadly applicable cellular therapies. Not applicable.

Imaging the fate of CAR-T cells in vivo

Despite the remarkable therapeutic efficacy of chimeric antigen receptor T (CAR-T) cell therapy in hematologic malignancies, its clinical translation in solid tumors remains impeded by challenges including insufficient intratumoral infiltration, tumor heterogeneity, and the immunosuppressive tumor microenvironment. Molecular imaging, which enables the visualization and quantitative analysis of the in vivo behavior of CAR-T cells, serves as a critical prerequisite for advancing the clinical application of CAR-T cell therapy in solid tumors. This review summarizes recent advances in molecular imaging techniques for monitoring the in vivo fate of CAR-T cells, covering their dynamic distribution, tumor recognition, and real-time functional activity. Additionally, the potential clinical value and current limitations of these approaches are discussed. It is proposed that this interdisciplinary integration may improve the precision of therapeutic response assessment and facilitate the optimization of personalized treatment strategies in the context of CAR-T cell therapy.

Emerging frontiers in adoptive cell therapies: engineering innovations, current challenges, and manufacturing perspectives