Researchers have produced perhaps the most detailed profile yet of a patient who developed a secondary CAR-T-cell-related malignancy following chimeric antigen receptor (CAR) T-cell therapy for multiple myeloma (MM).
The findings, published in Nature Medicine, help trace the crucial features and steps involved in the emergence of a new CAR-related T-cell lymphoma in a 63-year-old man after the use of a bispecific antibody and could offer clues for the future management of these cases, researchers said.
“Our analysis is one of the most granular assessments because we used longitudinal, spatially resolved, single-cell multiomic data to analyze the case,” said Maximilian Merz, MD, associate attending physician at Memorial Sloan Kettering Cancer Center. “Furthermore, it is, to the best of my knowledge, the first case after a bispecific antibody.”
His team has called the emergence of CAR-positive T-cell malignancies “a new and alarming concern” with the use of CAR-T therapy for relapsed or refractory MM and B-cell non-Hodgkin lymphoma. In November 2023, the U.S. Food and Drug Administration (FDA) reported 22 cases of T-cell malignancies in patients treated with CAR T-cell therapy, with special concern for T-cell lymphomas that are CAR expressing.
The case they’ve detailed, along with others, has revealed that a preexisting mutation of an epigenetic regulator arises in the hematopoietic cell compartment, “burdening” the myeloid and B-cell lineage. This can lead to a “permissive T-cell compartment,” the researchers said. After CAR treatment, this can bring about expansion of mutated T-cell clones, driven by the persistent antigen stimulation, “potentially through the CAR’s own target, such as soluble BCMA.”
“We propose that, in the context of a CAR-positive T-cell lymphoma, at least starting from the moment of its transduction, the CAR itself assumes the role of a constant signal provider, directly activating and supporting the expansion of the malignant T-cell clone,” researchers wrote.
The patient discussed in the paper had a three-year history of MM and was treated with ciltacabtagene autoleucel (cilta-cel) CAR-T therapy, his fifth line of treatment. Before the CAR infusion, he had achieved a partial remission (PR) after bridging therapy. Seven months later, he had a serologic relapse, but subsequent treatment with talquetamab, a bispecific antibody that binds to GPRC5D on myeloma cells and CD3 on T cells, led to a very good PR.
Nine months after the CAR-T therapy, the patient developed cutaneous and subcutaneous nodules on the face, neck, abdomen, and back, and occasionally on the arms and legs. He was diagnosed with nonnodal leukemic peripheral T-cell lymphoma with cutaneous and intestinal involvement.
Among the findings in the single-cell analysis, researchers found two different T-cell clones, one that was CD5 positive and one that was CD5 negative, and they were found to have different responses to dexamethasone, Dr. Merz said.
“Therefore, we hope to identify treatments in the future,” he said.
Preexisting mutations of TET2, a gene that regulates T-cell expansion, and CHK2, a DNA damage regulator, seem to have helped pave the way for the secondary malignancy, Dr. Merz said. These so-called CHIP mutations, for clonal hematopoiesis of indeterminate potential, have been present in other cases of CAR-T-regulated secondary malignancies as well, he said.
Still, the presence of these mutations might not be cause to forgo CAR-T therapy because the process is more complicated than that, Dr. Merz said.
“The interplay between all factors might have caused and be the prerequisite for malignant transformation,” he said.
Dr. Merz said the bispecific antibody also likely played a role.
“We think that T-cell stimulation caused by the bispecific antibody talquetamab was another very important factor that caused the malignant transformation,” he said.
“With increasing indications for CAR T-cell therapies and implementation within earlier treatment lines,” researchers wrote, “further research into the effects of sequential T cell-directed therapies following CAR T-cell treatment is critical.”
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Braun T, Rade M, Merz M, et al. Multiomic profiling of T cell lymphoma after therapy with anti-BCMA CAR T cells and GPRC5D-directed bispecific antibody [published online ahead of print, 2025 Feb. 21]. Nat Med. doi: 10.1038/s41591-025-03499-9.
Perspectives
In 2023, the FDA launched an investigation into the risk of T-cell lymphomas (TCLs) that develop from CAR T cells. Twenty-two cases have been documented among more than 27,000 CAR-T treatments, with at least five arising after cilta-cel treatment.1 To investigate the causes and molecular attributes of CAR-T lymphomas, Braun et al. characterized with high-dimensional molecular studies a patient who developed leukemic peripheral TCL after treatment with cilta-cel and talquetamab.
Interestingly, their studies showed that several cancer-promoting mutations predated CAR-T therapy. These mutations, TET2 and CHEK2, arose through clonal hematopoiesis, as they were found at a subclonal level in the patient’s apheresis sample. Braun et al. identified CAR integration at three sites; however, the significance of these mutations remains unclear, as they occurred in genes that have not been previously implicated in lymphomagenesis.
Secondly, talquetamab, a bispecific antibody that binds to CD3 on T cells and GPRC5D on myeloma cells, could have accelerated lymphomagenesis. The patient’s TCL progressed after this treatment and displayed an exhausted phenotype consistent with chronic antigenic stimulation. Up-regulation of T-cell antigen receptor pathways is known to characterize several TCLs,2 with PD1 deletion conferring more aggressive TCL phenotypes and checkpoint inhibition sometimes spurring TCL progression.2,3 Unfortunately, the patient’s malignancy progressed despite treatment with dexamethasone pulses.
Reports of TCL after CAR-T therapy remain rare and outnumbered by other secondary malignancies.4 Still, the work of Braun et al. and others provide several insights: First, some patients with B-cell malignancies could have elevated risk for CAR-T lymphomagenesis through clonal hematopoiesis. Screening for high-risk variants in the blood could help identify these patients before CAR engineering. The use of CAR-T therapy before mutagenic chemotherapy could also help to reduce CAR T-cell mutational burden. Second, immunotherapy after CAR-T treatment may unintentionally increase lymphomagenesis and should be monitored carefully. The best ways to treat CAR-associated TCLs remain unclear, but this case suggests that measures not traditionally used for peripheral TCLs may be relevant.
Jaehyuk Choi, MD, PhD
Director, Center for Cellular Therapies and Cancer Immunology
Professor and Vice Chair of Translational Research and Innovation
Simmons Comprehensive Cancer Center
Department of Dermatology
University of Texas Southwestern
Caroline S. Myers, MD
University of Pennsylvania Health System
Department of Dermatology
COI: Dr. Choi is a founder and board member of Moonlight Bio and has received consultant fees from Jansen.
References
- Hu J, Dunbar CE. T-cell lymphomas in recipients of CAR-T cells: assessing risks and causalities. Blood. 2024;144(24):2473-2481.
- Park J, Yang J, Wenzel AT, et al. Genomic analysis of 220 CTCLs identifies a novel recurrent gain-of-function alteration in RLTPR (p.Q575E). Blood. 2017;130(12):1430-1440.
- Wartewig T, Daniels J, Schulz M, et al. PD-1 instructs a tumor-suppressive metabolic program that restricts glycolysis and restrains AP-1 activity in T cell lymphoma. Nat Cancer. 2023;4(10):1508-1525.
- Elsallab M, Ellithi M, Lunning MA, et al. Second primary malignancies after commercial CAR T-cell therapy: analysis of the FDA Adverse Events Reporting System. Blood. 2024;143(20):2099-2105.
