CAR T: Autologous vs Allogeneic

CAR-T therapy snapshot

CAR-T therapy can yield remarkable—and sometimes lifesaving—benefits in certain patients with treatment-resistant blood cancers such as B-cell lymphoma and multiple myeloma, and is widely recognized as a breakthrough in cancer management.  A form of immunotherapy, CAR-T therapy harnesses the power of the patient’s own T cells to target antigens present on the surface of certain cancer cells. During manufacturing, a protein—a chimeric antigen receptor or CAR—is incorporated into the patient’s own T cells enabling them to recognize and destroy targeted malignant cells.

The CAR protein comprises three functional domains that act in concert: an extracellular domain that recognizes tumor antigens, a transmembrane hinge region that anchors the receptor, and an intracellular signaling domain that activates the T cell upon antigen binding.1 Activated CAR-T cells are not only directly cytotoxic to targeted cancer cells, they also proliferate and signal other immune system cells to join the battle against the malignancy—amplifying the antitumor response. 

CAR-T therapies can yield long-term―even lifelong―benefits after a single administration. Like native T cells, CAR-T cells can develop memory-like properties, allowing persistent activity against target cancer cells over time.2

CAR-T therapy utilizes two main sources of T cells:

  • Autologous T cells: Collected from the patient
  • Allogeneic T cells: Collected from a healthy donor

To date, all six CAR-T therapies approved by the FDA use autologous sources.3

Issues with autologous T cells

Despite stunning success in some patients, current autologous CAR-T therapies face daunting obstacles related to cost (≈$500,000/treatment), side effects (cytokine release syndrome and neurotoxicity, for instance), and variable cell quality, which can be compromised by the patient’s disease or previous therapies.4-7

Moreover, all currently approved CAR-T products require complex, multistep manufacturing. This process—often taking a month or more—includes T-cell collection, genetic modification, expansion, and reinfusion. This manufacturing process involves a lengthy ‘vein-to-vein’ time that can increase the risk for disease progression, especially in patients with aggressive disease.

Are allogeneic T cells the answer?

Allogeneic T-cell harvesting offers several important advantages, including the potential for reduced cost, simplified supply chain, and improved cell consistency and scalability.8 Unlike autologous therapy, “off-the-shelf” allogeneic CAR-T products are derived from healthy donors, manufactured in advance, and stored for immediate use. When needed, patients can be matched to available donor cells, enabling more rapid treatment initiation.9 This approach may also enable repeat dosing and more standardized product quality, potentially improving cost efficiency.10 Lower cost and greater availability could expand access, particularly in countries lacking the infrastructure to engineer autologous CAR T.

Although the allogeneic approach remains intriguing, it too faces major hurdles. The development of allogeneic CAR-T cells requires additional genetic modification to T cells to reduce immunogenicity.11 Graft-versus-host disease, in which donor T cells attack healthy host tissues, remains a major concern. Moreover, host-versus-graft rejection, characterized by rapid clearance of infused cells, may also limit efficacy. Other challenges include reduced in vivo persistence and ongoing manufacturing and scalability constraints.5,8,12,13

Off-the-shelf CAR-T cell availability offers intriguing advantages, but ensuring consistent potency, durability, and safety at scale remain unresolved issues.

Conclusion

Allogeneic CAR-T therapy holds some promise but remains in early clinical development. If key barriers—particularly immunogenicity and persistence—can be overcome, it may emerge as a more accessible, cost-effective, and scalable alternative to autologous CAR-T therapy for some patients.

References

  1. Labanieh, L., Majzner, R.G. & Mackall, C.L. Programming CAR-T cells to kill cancer. Nat Biomed Eng 2, 377–391 (2018). https://doi.org/10.1038/s41551-018-0235-9
  2. CAR T cells: engineering patients’ immune cells to treat their cancers. National Cancer Institute. March 10, 0222. Accessed July 11, 2024. https://www.cancer.gov/about-cancer/treatment/research/car-t-cells
  3. FDA investigating serious risk of T-cell malignancy following BCMA-directed or cd19-directed autologous chimeric antigen receptor (CAR) T cell immunotherapies. U.S. Food and Frug Administration. November 28, 2023. Accessed July 11, 2024.  https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-investigating-serious-risk-t-cell-malignancy-following-bcma-directed-or-cd19-directed-autologous
  4. Edward R. Scheffer Cliff et al., High Cost of Chimeric Antigen Receptor T-Cells: Challenges and Solutions. Am Soc Clin Oncol Educ Book 43, e397912(2023). DOI:10.1200/EDBK_397912
  5. Gajra A, Zalenski A, Sannareddy A, Jeune-Smith Y, Kapinos K, Kansagra A. Barriers to Chimeric Antigen Receptor T-Cell (CAR-T) Therapies in Clinical Practice. Pharmaceut Med. 2022 Jun;36(3):163-171. doi: 10.1007/s40290-022-00428-w
  6. Side effects of CAR T-cell therapy. BMTinfonet.org. June 2024. Accessed July 11, 2024. C:\Users\owner\Documents\TurboTax
  7. Challener C. Moving from autologous to allogeneic cell therapies: drivers and hurdles. Pharma’s Almanac. January 31, 2023. Accessed July 11, 2024. https://www.pharmasalmanac.com/articles/moving-from-autologous-to-allogeneic-cell-therapies-drivers-and-hurdles
  8. King, D. Engineered T-Cells: a look at autologous and allogeneic CAR-T cell immunotherapies. Allcells. June 12, 2020. Accessed July 11 2024. https://allcells.com/car-t-cell-therapy/
  9. Martínez Bedoya D, Dutoit V, Migliorini D. Allogeneic CAR T Cells: An Alternative to Overcome Challenges of CAR T Cell Therapy in Glioblastoma. Front Immunol. 2021 Mar 3;12:640082. doi: 10.3389/fimmu.2021.640082
  10. Allogeneic CAR-T —the next revolution in cell therapy. Allogene. Accessed July 12, 2024. https://allogene.com/allocar-t/
  11. Zhang P, Zhang G, Wan X. Challenges and new technologies in adoptive cell therapy. J Hematol Oncol. 2023 Aug 18;16(1):97. doi: 10.1186/s13045-023-01492-8
  12. Dhakal B, Chhabra S, Savani BN, Hamadani M. Promise and pitfalls of allogeneic chimeric antigen receptor therapy in plasma cell and lymphoid malignancies. Br J Haematol. 2022 Apr;197(1):28-40. doi: 10.1111/bjh.17904
  13. Depil, S., Duchateau, P., Grupp, S.A. et al. ‘Off-the-shelf’ allogeneic CAR T cells: development and challenges. Nat Rev Drug Discov 19, 185–199 (2020). https://doi.org/10.1038/s41573-019-0051-2