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T-Cell Lymphoma From CAR T-Cell Therapy—A New Safety Notice

1/11/24 JAMA Viewpoint

On November 28, 2023, a concerning safety signal was announced by the US Food and Drug Administration (FDA) Center for Biologics Evaluation and Research. Several patients undergoing chimeric antigen receptor (CAR) T-cell therapy for pediatric acute lymphocytic leukemia, non-Hodgkin lymphoma, and multiple myeloma developed T-cell lymphoma. The lymphoma in question contains the CAR construct, meaning that the drug product itself has transitioned into a malignancy. This finding, although rare (the FDA has yet to release the number of reports), has significant implications for all CAR T-cell therapy development programs. Herein is outlined what is known, residual uncertainties, and implications.1


The FDA’s acknowledgment of a safety concern represents an important regulatory event. It is probable the T-cell lymphomas in question are causally related to infusion of the CAR T-cell product, given that the genetic signature of the construct is easily detectable in the malignant clone. That this has occurred for all approved CAR T-cell products suggests it is a class effect and not confined to the specific manufacturing process of a single company or the specific costimulatory domain of a single CAR T-cell therapy.1 In fact, the FDA suspects this will be true for all CAR T-cell therapies that use integrating vectors, such as retroviral or lentiviral vectors, although admittedly, it may not occur for ongoing investigational products that use RNA, resulting in only transient expression of the CAR.


The real incidence remains unknown but must be rare. Reports of CAR T-cell transformation remain scarce in the reported literature. Tens of thousands of products must have been administered since the original approval of tisagenlecleucel in 2016.2 One preliminary analysis found just 12 cases of T-cell lymphoma reported in 17 700 infusions, a rate of 0.068%.3 Yet this may be an underestimate because sequencing is unlikely to be universally performed when a subsequent T-cell lymphoma is observed.


The net effect of CAR T-cell therapy for approved indications likely remains favorable.1 For diffuse large B-cell lymphoma, randomized data show that some CAR T-cell products result in improved overall survival over autologous stem cell transplant.4 This fact alone means that any harms of CAR T-cell therapy must be smaller than benefits. Yet notably for myeloma, overall survival was not improved (to date) in randomized trials, nor in mantle cell lymphoma or follicular lymphoma. Some caution is required for cancer types that lack randomized data showing mortality benefit. Some investigators are studying CAR T-cell therapy in premalignant cases, such as smoldering myeloma (NCT05767359). These investigations should proceed with utmost caution, given potential to harm patients with lengthy life expectancy.


For forthcoming CAR T-cell products, approvals would ideally be based on data from randomized clinical trials. Initial approvals of tisagenlecleucel and other CAR T-cell therapies were based on nonrandomized data in pediatric acute lymphocytic leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma, and follicular lymphoma. Single-arm trials allow for these products to be offered earlier to patients who have exhausted all other options. Likely a greater reliance on randomized clinical trials is needed in confirmatory trials, permitting conversion from accelerated to regular approval, particularly because the product is offered earlier in disease courses.


The risk-benefit of CAR T-cell therapy pursued in noncancer indications or cancer with long survival times is entirely uncertain. With added time, the propensity for the cellular product to transform into malignancy—particularly if it is persistent—will increase. For diseases with short survival times, such as the aforementioned, it is likely the net benefit of CAR T-cell therapy will be positive, but for diseases such as lupus5 or myasthenia gravis in which CAR T-cell therapy is being assessed, it is likely that harms may swell with decades of follow-up.


It is commendable that the FDA issued the safety alert promptly. Therapy with CAR T cells remains a promising avenue of investigation (Table),6 and studies in patients with cancer and short life expectancy should not be halted. Yet patients should provide additional consent to acknowledge this risk. Drug development in noncancer conditions requires reassessment by institutional review boards pending better characterization of the risk.

Table.  Pivotal Trials Testing CAR T-Cell Therapies Leading to FDA Approval for Hematologic and Oncologic Indications


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Further biological studies are needed to understand the mechanism of malignant transformation and whether it can be abrogated by so-called kill switches or other mechanisms to remove or destroy the CAR T cells after infusion and response. Some non-DNA methods of CAR engineering are ongoing,7 and these may better optimize the benefit-to-harm balance of CAR T-cell therapy.


The announcement by the FDA of the safety signal that the CAR T-cell product can itself become a cancer is a noteworthy step in the history of this product. This ability appears to be a class effect, affecting all products and approvals. Although rare, the malignant transformation of a cellular therapy is a concerning safety signal, and diligent efforts should be made to monitor it, ascertain the true incidence, and research efforts to avoid the risk. Many lives have been saved by CAR T-cell therapy and the product likely retains a net benefit in most approved indications.



Article Information

Corresponding Author: Vinay Prasad, MD, MPH, Department of Epidemiology and Biostatistics, UCSF Mission Bay Campus, Mission Hall: Global Health and Clinical Sciences Bldg, 550 16th St, Second Floor, San Francisco, CA 94158 (vinayak.prasad@ucsf.edu).

Published Online: January 11, 2024. doi:10.1001/jama.2023.27885


Conflict of Interest Disclosures: Dr Prasad reported receiving research funding from Arnold Ventures through a grant made to UCSF; receiving royalties for books and writing from Johns Hopkins Press, MedPage, and the Free Press; consulting for UnitedHealthcare and OptumRx; hosting podcasts for Plenary Session, VPZD, and Sensible Medicine; writing newsletters for Sensible Medicine, the Drug Development Letter, and VP’s Observations and Thoughts; and receiving subscriber fees from YouTube, Patreon, and Substack outside the submitted work.


References

1.

US Food and Drug Administration. FDA investigating serious risk of T-cell malignancy following BCMA-directed or CD19-directed autologous chimeric antigen receptor (CAR) T cell immunotherapies. Published November 28, 2023. Accessed December 1, 2023. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-investigating-serious-risk-t-cell-malignancy-following-bcma-directed-or-cd19-directed-autologous

2.

Prasad  V.  Immunotherapy: tisagenlecleucel—the first approved CAR-T-cell therapy: implications for payers and policy makers.   Nat Rev Clin Oncol. 2018;15(1):11-12. doi:10.1038/nrclinonc.2017.156PubMedGoogle ScholarCrossref

3.

Liu  A. FDA investigates “serious risk” of secondary cancer following CAR-T treatment. Fierce Pharma. Published November 28, 2023. Accessed December 1, 2023. https://www.fiercepharma.com/pharma/fda-investigates-serious-risk-secondary-cancer-following-car-t-therapy-treatment

4.

Kamdar  M, Solomon  SR, Arnason  J,  et al; TRANSFORM Investigators.  Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial.   Lancet. 2022;399(10343):2294-2308. doi:10.1016/S0140-6736(22)00662-6PubMedGoogle ScholarCrossref

5.

Mackensen  A, Müller  F, Mougiakakos  D,  et al.  Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus.   Nat Med. 2022;28(10):2124-2132. doi:10.1038/s41591-022-02017-5PubMedGoogle ScholarCrossref

6.

Haslam  A, Høeg  TB, Prasad  V.  Estimation of eligibility for and response to CAR-T therapy in the United States.   Blood Adv. Published online December 1, 2023. doi:10.1182/bloodadvances.2023011184PubMedGoogle ScholarCrossref

7.

Fesnak  AD, June  CH, Levine  BL.  Engineered T cells: the promise and challenges of cancer immunotherapy.   Nat Rev Cancer. 2016;16(9):566-581. doi:10.1038/nrc.2016.97PubMedGoogle ScholarCrossref


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