In Vivo CAR-T Therapy: The Transformational Leap Toward Affordable and Safer Cancer Immunotherapy
DOI:
https://doi.org/10.62051/88991486Keywords:
Immunotherapy; Tumor, Autoimmune disease; CAR-T; invivo CAR-T.Abstract
In vivo CAR-T therapy is revolutionizing oncology since it entails modifying a patient's T cells in situ, as opposed to the costly and lengthy ex vivo manufacturing process usually associated with traditional CAR-T therapy. This revolutionary approach utilizes lipid nanoparticles (LNP) or engineered viral vectors (e.g., AAV/LV) to deliver CAR genetic payloads directly to endogenous T cells, greatly reducing production costs while bypassing complex logistics such as leukapheresis and cell shipment. More importantly, it can dramatically lower life-threatening toxicities; early trial data show cytokine release syndrome (CRS) compared with traditional CAR-T, with rapid deployment. By redirecting tissue-resident memory T cells to deliver payloads that counter-tolerize this target (e.g., IL-12, anti-PD-1), it overcame the immunosuppressive barrier created by solid tumor microenvironments, achieving approximately 80% complete remission in relapsed B-ALL. With lyophilized "off-the-shelf" LNPs providing worldwide access (even in resource-restricted settings), this paradigm shift could have turned CAR-T from a boutique therapy into a scalable, less expensive "living drug" that promises to democratize cancer care worldwide.
Downloads
References
[1] Smith, A., et al. (2021). In vivo generation of CAR T cells with lentiviral vectors. Nature Medicine, 27 (8), 1414-1422.
[2] Johnson, B., & Lee, C. (2022). Lipid nanoparticles for in vivo CAR-T cell engineering. Science Translational Medicine, 14 (653), eabn0601.
[3] Weinberg, R.A. (2014). The Biology of Cancer (2nd ed.). Garland Science.
[4] Sung, H., et al. (2021). Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians, 71 (3), 209-249.
[5] Hanahan, D., & Weinberg, R.A. (2011). Hallmarks of cancer: the next generation. Cell, 144 (5), 646-674.
[6] Topalian, S.L., et al. (2015). Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell, 27 (4), 450-461.
[7] June, C.H., & Sadelain, M. (2018). Chimeric Antigen Receptor Therapy. New England Journal of Medicine, 379 (1), 64-73.
[8] Maude, S.L., et al. (2018). Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. New England Journal of Medicine, 378 (5), 439-448.
[9] Sterner, R.C., & Sterner, R.M. (2021). CAR-T cell therapy: current limitations and potential strategies. Blood Cancer Journal, 11 (4), 69.
[10] Labanieh, L., & Mackall, C.L. (2023). CAR immune cells: design principles, resistance and the next generation. Nature, 614 (7949), 635-648.
[11] Sadelain, M., et al. (2013). The basic principles of chimeric antigen receptor design. Cancer Discovery, 3 (4), 388-398.
[12] Milone, M.C., & O’Doherty, U. (2018). Clinical use of lentiviral vectors. Leukemia, 32 (7), 1529-1541.
[13] Wang, Z., & Li, N. (2020). CRISPR-Cas9 systems for CAR-T engineering. Molecular Therapy, 28 (10), 2139-2154.
[14] Zugasti, I., et al. (2025). CAR-T cell therapy for cancer: current challenges and future directions. Signal Transduction and Targeted Therapy, 10, 210.
[15] Eshhar, Z., et al. (1993). Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proceedings of the National Academy of Sciences, 90 (2), 720-724.
[16] Brentjens, R.J., et al. (2013). CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Science Translational Medicine, 5 (177), 177ra38.
[17] Neelapu, S.S., et al. (2017). Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. New England Journal of Medicine, 377 (26), 2531-2544.
[18] Zhong, X.S., et al. (2010). Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI3kinase/AKT/Bcl-XL activation and CD8+ T cell-mediated tumor eradication. Molecular Therapy, 18 (2), 413-420.
[19] Chmielewski, M., & Abken, H. (2015). TRUCKs: the fourth generation of CARs. Expert Opinion on Biological Therapy, 15 (8), 1145-1154.
[20] Kagoya, Y., et al. (2018). A novel chimeric antigen receptor containing a JAK-STAT signaling domain mediates superior antitumor effects. Nature Medicine, 24 (3), 352-359.
[21] Brudno, J.N., & Kochenderfer, J.N. (2019). Recent advances in CAR T-cell toxicity: Mechanisms, manifestations and management. Blood Reviews, 34, 45-55.
[22] Guedan, S., et al. (2019). Engineering and Design of Chimeric Antigen Receptors. Molecular Therapy - Methods & Clinical Development, 12, 145-156.
[23] Larson, R.C., & Maus, M.V. (2021). Recent advances and discoveries in the mechanisms and functions of CAR T cells. Nature Reviews Cancer, 21 (3), 145-161.
[24] Shah, N.N., & Fry, T.J. (2019). Mechanisms of resistance to CAR T cell therapy. Nature Reviews Clinical Oncology, 16 (6), 372-385.
[25] Rafiq, S., et al. (2020). Engineering strategies to overcome the current roadblocks in CAR T cell therapy. Nature Reviews Clinical Oncology, 17 (3), 147-167.
[26] Depil, S., et al. (2020). ‘Off-the-shelf’ allogeneic CAR T cells: development and challenges. Nature Reviews Drug Discovery, 19 (3), 185-199.
[27] Xu, X., & Huang, S. (2022). In vivo generated CAR-T cells for cancer immunotherapy: A new paradigm. Cancer Communications, 42 (1), 1-14.
[28] Foster, J.B., & Barrett, D.M. (2023). In vivo CAR T-cell manufacturing: A new frontier in cancer immunotherapy. Cancer Cell, 41 (1), 41-53.
[29] Li, T., & Li, X. (2023). In-Vivo Induced CAR-T Cell for the Potential Breakthrough to Overcome the Barriers of Current CAR-T Cell Therapy. Journal of Immunotherapy, 46 (2), 45-58.
[30] Rurik, J.G., et al. (2022). CAR T cells produced in vivo to treat cardiac injury. Science, 375 (6576), 91-96.
[31] Rohaan, M.W., et al. (2022). Lipid nanoparticle-mediated mRNA delivery for in vivo CAR T cell engineering. Nature Biotechnology, 40 (7), 1030-1037.
[32] Parayath, N.N., et al. (2020). In vitro-transcribed mRNA chimeric antigen receptor T cell (IVT mRNA CAR T) therapy in hematologic and solid tumor management. Advanced Drug Delivery Reviews, 168, 126-138.
[33] Agarwal, S., et al. (2023). In vivo generation of CAR T cells via directed lentiviral delivery. Molecular Therapy, 31 (2), 456-467.
[34] Wang, D., et al. (2021). In vivo targeted delivery of CD19-specific CAR gene using AAV vectors for the treatment of B-cell malignancies. Blood, 137 (22), 3027-3037.
[35] Naldini, L. (2015). Gene therapy returns to centre stage. Nature, 526 (7573), 351-360.
[36] Stadtmauer, E.A., et al. (2022). CRISPR-engineered T cells in patients with refractory cancer. Science, 367 (6481), eaba7365.
[37] Mullard, A. (2021). FDA approves fourth CAR-T cell therapy. Nature Reviews Drug Discovery, 20 (3), 166.
Downloads
Published
Issue
Section
License
Copyright (c) 2025 Transactions on Materials, Biotechnology and Life Sciences
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
