2026· Advances in Pharmacology· Vol 106, pp.
213-251
· 1 citation
Medicine
TL;DR
A review of the biological rationale, delivery engineering, immunological barriers, CAR payload design, early clinical evidence, and future directions of this field focuses on the pharmacological principles that distinguish in vivo from ex vivo approaches and on the transformative potential for indications that lie beyond the current reach of conventional CAR T cell therapy.
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.
This review highlights key engineering strategies enabling in vivo CAR T-cell generation, summarizes emerging clinical research and development, and discusses future opportunities for expanding in vivo CAR T-cell therapies as scalable immunotherapy platforms.
Janani Gopalakrishnan, B. Rathod, Sachin Puri· International Immunopharmaco...· 0 citations
If in-vivo CAR-T therapy 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.
Lia Bhatia· American Journal of Student...· 0 citations
The intrinsic trade-off between therapeutic durability and biosafety across distinct delivery platforms is discussed, along with the necessity that their clinical translation hinges on systematic optimization of delivery precision, immune compatibility, and expression controllability.
Meifen Luo, Kai Liao, Jinxi Chang et al.· Advances in Materials· 0 citations
Nonviral NPs are poised to redefine CAR therapy by enabling scalable, off-the-shelf immune interventions for cancer, autoimmune, and fibrotic diseases.
Ke Huang, Hao Wang, Tao Zhu et al.· Biomaterials· 1 citation
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.
Markus Barden, D. Harrer, Hinrich Abken· Expert Opinion on Biological...· 0 citations
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