Summary Cancer immunotherapy has made significant advancements, as immune checkpoint inhibitors and cytokines are widely applied in the clinic. Nonetheless, these therapies are often challenged by severe side effects arising from inappropriate activation of the immune system or systemic toxicity. Herein, we constructed a tumor-selective, safe therapeutic gene cassette specifically activated by NF-κB to produce cytokine IL-15 and microRNAs silencing two key immune checkpoints, PD-L1 and CD47. High NF-κB activity in cancer cells drove expression of the cassette to produce IL-15 and suppress PD-L1 and CD47, while low basal NF-κB rendered the cassette silent in most normal cells. This design simultaneously activated and enhanced adaptive and innate immunity. A recombinant adeno-associated virus (AAV2) delivering the cassette showed significant antitumor effects, favorable tumor selectivity, and biosafety across multiple murine solid tumor models. Consequently, this treatment may offer a potentially more effective and safer immunotherapy against cancers in the future.
Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of several hematological malignancies, but its broader application remains constrained by the complexity, cost, and time required for conventional ex vivo manufacturing.
In vivo
CAR T-cell therapy has emerged as a promising next-generation strategy that aims to generate CAR T cells directly within the patient through targeted delivery of CAR-encoding genetic information to endogenous T cells. This approach has the potential to simplify treatment workflows, shorten manufacturing timelines, reduce production costs, and improve the accessibility of CAR-based immunotherapy. In this review, we summarize the conceptual evolution from ex vivo to
in vivo
CAR T-cell therapy and discuss major delivery platforms for
in vivo
CAR T-cell generation, including engineered lentiviral vectors (LVs), adeno-associated viral vectors, lipid nanoparticles, polymeric nanoparticles, extracellular vesicles, and fusogenic nanovesicles. We further examine key translational challenges and corresponding optimization strategies, including approaches to improve T-cell targeting specificity and delivery controllability, reduce vector immunogenicity, enhance CAR expression persistence, mitigate safety concerns associated with ectopic transduction or genomic integration, and potentially overcome the physical, antigenic, and immunosuppressive barriers encountered in solid tumors. Finally, we summarize early clinical trial progress and discuss future directions for improving the safety, efficacy, and translational potential of
in vivo
CAR T-cell therapy. Overall,
in vivo
CAR T-cell therapy represents an important extension of adoptive cell therapy and may reshape the development and clinical implementation of cell-based immunotherapies.
Next-generation engineering strategies are being designed to overcome the obstacles that constrain CAR-T-cell efficacy in solid tumors and to guide the development of safer and more effective therapeutic platforms.
Zi-Yan Kong, Jin-Ke Wang· Frontiers in Immunology· 0 citations
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