Experts comment on FDA report on risk of T-cell malignancy  

Cell and gene therapy

The International Society for Cell & Gene Therapy (ISCT) has announced the publication in Nature Medicine of an expert consortium commentary addressing a recent statement from the US Food & Drug Administration (FDA) that it is investigating serious risk of T-cell malignancy in patients who received treatment with BCMA- or CD19-directed autologous CAR-T cell immunotherapy. 

ISCT, the global society of clinicians, researchers, regulators, technologists, and industry partners dedicated to the translation of cell and gene therapy (CGT) into safe and effective therapies to improve patients’ lives, aligns with the FDA in support of the need for thorough investigation and transparency. 

ISCT and its leaders firmly agree that the benefits of CAR-T therapies continue to outweigh potential risks in the vast majority of cases and recommends that centres with cell therapy expertise should continue to make commercial CAR-T products available to patients when it appears to be the best option available.  

Emphasising that 34,000 patients worldwide have received commercially available CAR-T cell immunotherapies, the commentary notes that the observed rate of 20 reported cases of T cell malignancies is notably lower than that reported for more conventional alternative treatments. The true nature and frequency of these malignancies are yet to be confirmed and important patient characteristics such as age, prior, immune status, whether the CAR gene is present in the T cell lymphomas, the landscape of genetic mutations carried by patients in these case, and other clinical features such as the time from CAR-T infusion to the development of T cell lymphoma, are unknown and need to be taken into consideration to fully evaluate the greater risk of these therapies.  

The expert consortium

The commentary led by ISCT in collaboration with leaders from American Society for Transplantation and Cellular Therapy (ASTCT), the European Society for Blood and Marrow Transplantation (EBMT), the Center for International Blood and Marrow Transplant Research (CIBMTR), and the Parker Institute for Cancer Immunotherapy (PICI), and immunotherapy developers and clinicians, follows the recent statement from the FDA that there are risks of malignancies with all currently approved BCMA-directed and CD19-directed genetically modified autologous CAR-T cell immunotherapies. These include tisagenlecleucel (Kymriah), lisocabtagene maraleucel (Breyanzi), axicabtagene ciloleucel (Yescarta), brexucabtagene autoleucel (Tecartus), Idecabtagene vicleucel (Abecma), and ciltacabtagene autoleucel (Carvykti). 

Speaking on the recent FDA statement, Bruce Levine, ISCT Immediate Past President and Lead Author on the publication, stated: “The fundamental question from this report is whether or not there is a causal link between CAR-T therapy and these rare T cell malignancy cases and in how many patients. Currently, there are too many unknown factors related to the 20 reported cases making it premature to establish the magnitude of what appears to be a very low risk. In alignment with the FDA’s stance, we maintain that the benefits of CAR-T therapies still outweigh the potential risks in the majority of cases. 

“Risks from CAR-T cell therapy should be contextualised against other standard treatment modalities such as chemotherapy and radiotherapy. These therapies, which exhibit substantial long-term side effects, including genotoxicity and an increased predisposition to secondary cancers, have significantly higher rates of subsequent malignancies than the rate reported for patients following CAR-T cell immunotherapies. In the interest of patients and patient safety, it is of the utmost importance that we continue to offer patients access to these life-saving therapies while simultaneously conducting thorough investigations.” 

The FDA hopes to provide the community with additional information by the first part of 2024. 

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