The risk of developing new tumours after CAR-T therapy has been described as small
American researchers analysed data from more than 700 patients treated with CAR-T-lymphocytes and concluded that their risk of developing new tumours, including those directly related to the therapy, was low. A report of the work is published in The New England Journal of Medicine.
The technology of T-leukocytes with a chimeric antigenic receptor (CAR-T-lymphocytes) has become a breakthrough in the treatment of some cancers, allowing in experiments to achieve a complete cure for many patients (we told in detail about this technology in the material "Chimera against cancer"). Only six CAR-T drugs have reached clinical use so far, all of them directed against CD19 or BCMA antigens and intended for therapy of B-cell neoplasms (leukaemia and lymphoma). Despite significant successes, there are concerns about the long-term safety of such treatments. For example, in November 2023, the US Food and Drug Administration (FDA) reported that it was collecting information on cases of T-cell lymphomas that developed de novo after the use of commercial CAR-T drugs to further evaluate their safety. Due to the small number of case reports, it is difficult to assess the actual risk of these cases.
To gain more detail on this issue, Stanford University researchers led by Ash Alizadeh and David Miklos audited the outcomes of all CAR-T therapies administered at the university's medical centre from 4 February 2016 to 15 January 2024. During this period, 724 patients received 791 infusions of therapeutic T cells. In 96.6 per cent of cases, these were CAR-T, while the remainder were cytokine-induced T-killers, cytotoxic T lymphocytes and T cells with improved receptor affinity for specific peptides.
Over a median follow-up period of 15 months, 25 new tumours were identified. 14 of these were haematological, with 13 associated with myelodysplastic syndrome or acute myeloid leukaemia and only one turned out to be a T-cell lymphoma. The remaining 11 neoplasms were solid and included four melanomas, two prostate carcinomas, two ductal carcinomas of the breast, one each of endometrial and lung adenocarcinoma, and one metastatic mesothelioma. The cumulative incidence of new haematological neoplasms over three years was 6.5 per cent.
The only T-cell lymphoma was reported in a 59-year-old female patient who received CD19-CAR-T-lymphocytes (axicabtagene ciloleucel, axi-Cel) for stage IV therapy-resistant diffuse large B-cell lymphoma positive for Epstein-Barr virus (EBV). It is noted that the woman suffered from psoriasis and eosinophilic fasciitis, for which she had been receiving a variety of immunotropic drugs for three years. A new tumour was detected on day 54 after axi-Cel treatment, and the initially debilitated patient died eight days later.
Her biosamples, including bone marrow biopsy specimens and both tumours at different stages of the disease, were analysed using a variety of cytological, molecular and genetic methods. It turned out that the woman's B- and T-cell lymphomas had different immunophenotypes and genomic profiles, but both were positive for EBV and associated with mutations of the NMT3A and TET2 genes in hematopoietic stem cells. No evidence of oncogenic integration of the vector lentivirus used to produce CAR-T lymphocytes could be detected. Based on this, the researchers concluded that the development of both tumours was based on the linear accumulation of mutant haematopoietic clones (TET2 deletion → DNMT3A R882C mutation → TET2 L1212fs*15 mutation) and EBV activation under immunosuppression; the contribution of CAR-T therapy is unlikely.
Considering that CAR-T-lymphocytes can cure at least half of patients who failed multiple sessions of chemotherapy, the risk of developing new tumours on its background is low and is not always related to the technology of obtaining therapeutic cells, the authors conclude.