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, thus deserving its recognition as a breakthrough paradigm for 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. In the manufacturing of CAR-T cells, a protein—a chimeric antigen receptor or CAR—is incorporated into the patient’s own T cells to help them target and destroy cancerous invaders.

The CAR protein comprises 3 domains that act in concert: one sits on the outside of the T-cell and recognizes antigens on cancer cells, a transmembrane hinge component anchors the CAR to the T-cell surface, and an intracellular component activates when the extracellular component attaches to a targeted antigen on the cancer cells surface.1 Activated CAR-T cells are not only directly cytotoxic to cancer cells, they also proliferate and signal other immune system cells to join the battle against the targeted malignant cells. 

CAR-T therapies can yield long-term―even lifelong―benefits after a single administration. Normally, when T cells target harmful invaders the first time, they are reprogrammed to remember these invaders the second time around and thereafter. CAR-T cells act similarly and, as result, their activity against a specific cancer cell can persist for a patient’s lifetime.2

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

  • Autologous T cells: Those derived from the patient
  • Allogeneic T-cells: Those derived 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 in terms of cost (≈$500,000/treatment); side effects (cytokine release syndrome and neurotoxicity, for instance), and cell quality, which can be compromised by the patient’s disease or previous therapies.4-7

Moreover, all currently approved CAR-T products require the orchestration of several logistically complex and time-consuming manufacturing steps. The process—often requiring a month or more to complete—involves extracting cells from the patient, genetically modifying the extracted T cells, and growing the cells into large quantities so they can be reintroduced back into the patient in sufficient amounts to induce a meaningful therapeutic response. 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 volume and quality.8 In contrast to the use of autologous T cells, the ‘off-the-shelf’ allogeneic CAR-T approach uses cells that have been obtained from healthy donors, then genetically modified and stored in scalable batches, ready to be used without delay. When a patient requires CAR-T therapy, clinicians test the patient’s tissue type to find the best match among the stored donor cells, providing the opportunity for more timely treatment.9 The allogeneic approach also can provide high yields of fully functional cells that allow more cost-efficient repeat dosing when needed.10  Owing to both a lower cost and a readily available inventory, access would be greatly increased, particularly in countries that lack the appropriate 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 Indeed, graft-versus-host disease—in which donor T cells target patients’ health tissue—represents a major barrier.  Other lurking barriers include host immune rejection manifested by the rapid elimination of the allogeneic cells by the recipient’s immune system; potentially low in vivo CAR-T persistence; and manufacturing challenges.5,8,12,13 While allogeneic CAR-T cells offer the advantage of immediate availability of cryopreserved batches, there are still manufacturing limitations and logistical complexities involved in producing and delivering these cells at scale while ensuring consistent quality and potency.

Conclusion

While allogeneic CAR-T therapy shows promise, it is still in early clinical development. As research progresses—and if major immunogenic obstacles can be overcome—allogeneic CAR-T therapy may offer a more readily available, cost-effective, and versatile alternative to standard autologous CAR-T therapy.

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