Chimeric antigen receptor (CAR) T-cell therapies are a novel class of targeted and personalized immunotherapy which have shown remarkable success to date in treating certain hematological malignancies, including certain types of leukemia and lymphoma. There are currently six commercially available CAR T-Cell therapies: Abecma, Breyanzi, Kymriah, Tecartus, Yescarta, and Carvykti (Ghosh, 2023). There are a further 250 therapies under development, of which 81% are using an autologous approach and 19% are using an allogeneic approach, and with the global CAR-T cell therapy market growing at an annual rate of 21% (Mikulic, 2023), this therapeutic class looks well positioned to deliver significant patient impact in the coming years.
Despite this promise, there are significant challenges associated with this therapeutic class. In November 2023, the FDA announced they were investigating several reports of T-cell malignancies, specifically CAR-positive lymphoma, in patients treated with BCMA- or CD19-directed autologous CAR T-cell immunotherapies. The risk of secondary malignancies is applicable to all gene therapy products with integrating vectors (lentiviral and retroviral) and are labeled with a class warning in the U.S. prescribing information. To combat the known malignancy risks, the FDA’s initial approval of these products include 15-year long-term follow-up observational studies with suggested life-long monitoring for new malignancies (FDA's Center for Biologics Evaluation and Research, 2023). However, follow-up data, particularly the observations around T-cell malignancies, highlight the need for a paradigm shift in cell therapy design to reduce the risk of such malignancies.
Safety switch technologies have been hailed as the most likely solution to the problems arising in CAR T-Cell therapies. Safety switches are genetic inserts that have minimal to no effect on the infused cells but can be activated when a drug is introduced into the patient. The gene activation in a suicide switch causes cell death in the therapeutic cells to prevent them from causing malignancies and other potential side effects. There are several different safety switch categories, including logic-gated, on/off, switchable, multi-targeting, and armored safety switches (Verma et al., 2023). Examples of such safety switches include the on/off safety switch created by UNC Lineberger Comprehensive Cancer Center, named inducible caspase-9 (iC9), which is activated by the drug rimiducid (McNulty, 2021). There are also HSV-TK-based suicide switches that are triggered by the drug ganciclovir. However, HSV-TK treatments are limited in use as they cannot be used in immunocompromised patients (Zheng et al., 2021).
To address the FDA’s concerns of uncontrolled proliferation and genetic mutations that can lead to malignancies, Pluristyx is pleased to offer our proprietary FailSafe® safety switch as a fundamental component of the panCELLa platform for iPSC and Cell Therapy development. The FailSafe® safety switch technology links the expression of a drug-inducible suicide gene into a gene absolutely essential for division within a cell division essential locus (CDEL). As cells require the CDEL to divide and expand, the FailSafe® insertion can effectively eliminate only actively dividing cells among transplanted cells, ensuring that healthy non-proliferating cells remain intact. In other words, the unique FailSafe® approach ensures that differentiated therapeutic cells remain unharmed, allowing them to continue providing benefits to patients while selectively removing proliferating cells that are not performing as intended. FailSafe® utilizes a homozygous strategy to ensure that both alleles of the CDEL gene carry the suicide gene, guaranteeing the death of dividing cells.
As an exclusively licensed technology developed by one of the scientific founders of panCELLa, Andras Nagy, Pluristyx offers clear Freedom to Operate from idea to commercialization for our therapeutic partners. Try Pluristyx’s PluriBank cells today, complete with our FailSafe® edits, to improve the safety profile of your therapy.
References
- FDA's Center for Biologics Evaluation and Research. (2023, November 28). FDA Investigating Serious Risk of T-cell Malignancy Following BCMA-Directed or CD19-Directed Autologous Chimeric Antigen Receptor (CAR) T cell Immunotherapies. FDA. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-investigating-serious-risk-t-cell-malignancy-following-bcma-directed-or-cd19-directed-autologous
- Ghosh, S. (2023, March). Chimeric Antigen Receptor (CAR) T-Cell Therapy Market. Future Market Insights. https://www.futuremarketinsights.com/reports/chimeric-antigen-receptor-t-cell-therapy-market#:~:text=The%20global%20chimeric%20antigen%20receptor
- Mikulic, M. (2023, April 3). Global market size CAR T-cell therapies 2030 forecast. Statista. https://www.statista.com/statistics/1098399/global-market-revenues-in-car-t-cell-therapies/
- McNulty, R. (2021, March 11). Experimental Safety Switch Has Potential to Reduce CAR T Side Effects. AJMC. https://www.ajmc.com/view/experimental-safety-switch-has-potential-to-reduce-car-t-side-effects
- National Cancer Institute. (2018). Surveillance, Epidemiology, and End Results Program. SEER. https://seer.cancer.gov/
- Verma, M., Obergfell, K., Topp, S., Panier, V., & Wu, J. (2023). The next-generation CAR-T therapy landscape. Nature Reviews Drug Discovery, 22(10), 776–777. https://doi.org/10.1038/d41573-023-00140-7
- Zheng, Y., Nandakumar, K. S., & Cheng, K. (2021). Optimization of CAR-T Cell-Based Therapies Using Small-Molecule-Based Safety Switches. Journal of Medicinal Chemistry, 64(14), 9577–9591. https://doi.org/10.1021/acs.jmedchem.0c02054