Emerging Strategies Aim to Enhance Safety and Monitoring in CAR T-Cell Therapy

In an interview with OncLive®, Samir Parekh, MBBS, emphasized that although CAR T-cell therapy remains a highly successful treatment option for select patients with hematologic malignancies, rare complications require systematic monitoring and management. He highlighted the potential role of strategies such as drug screening platforms, kill-switch designs, and surveillance for clonal hematopoiesis of indeterminate potential (CHIP) mutations to improve safety and guide individualized care.

Parekh also discussed the use of mogamulizumab, an anti-CCR4 antibody, in the treatment of secondary T-cell lymphoma, underscoring the importance of patient selection and multidisciplinary monitoring. Looking ahead, he pointed to the need for future research focused on developing safer CAR T-cell constructs with built-in kill switches and gaining a deeper understanding of the biological mechanisms driving malignant transformation and secondary neoplasms.

In the first part of the interview, Parekh detailed findings from a case study where clinicians successfully repurposed the anti-CCR4 antibody mogamulizumab (Poteligeo) in combination with chemotherapy for a patient with CAR-positive peripheral T-cell lymphoma following CAR T-cell therapy for multiple myeloma.

Parekh is a professor of Medicine (Hematology and Medical Oncology) and Oncological Sciences at the Icahn School of Medicine at Mount Sinai in New York, New York.

OncLive: How can strategies like drug screening platforms, kill-switch designs, and CHIP mutation surveillance be integrated into managing CAR T-cell therapy complications?

Parekh: [CAR T] is a very successful therapy, and patients do benefit. In rare cases where patients experience complications, we have to monitor them carefully and treat them in a systematic way. These array-type approaches, where we can systematically screen for drugs and give custom therapies, will actually give us a kill switch for the [CAR T-cell therapy], which is not in current [CAR T-cell therapy] designs, but can be very useful, not just for T-cell lymphomas, but potentially other complications such as hemophagocytic lymphohistiocytosis [HLH] and rare neurotoxicity that has also been noted with anti-BCMA [CAR T-cell therapy], so there are broader implications.

Additionally, epigenetic modifiers, which are [CHIP] mutations, are seen more commonly, but we don't currently have any systematic way of screening patients or even monitoring patients for this. I would suggest at least monitoring would be wise, because if we see clonal expansion of these after [CAR T], perhaps these patients need to have greater surveillance, not just for lymphoma, but also other secondary neoplasms.

What is the mechanism of action of the anti-CCR4 agent? What clinical outcomes were observed with its use in this patient?

The anti-CCR4 antibody is a drug called mogamulizumab. It is a monoclonal antibody that is quite safe and effective, and it is used routinely for [adult T-cell leukemia/lymphoma] that's associated with HTLV-1. The main [adverse] effect [AE] with this agent is some patients get allergic reactions that are cutaneous rashes, and potentially, it can lead to further immunosuppression. We monitored the patient in conjunction with the dermatologist. I would suggest, if people are going to use this medicine, they would first screen the patients for CCR4 expression, and if they're administering [mogamulizumab], please consult your dermatology colleagues to monitor for AEs in a careful manner.

What makes this novel approach a first in hematologic cancer research, and why is this case significant?

This approach is going to be useful not just for the rare patient with T-cell lymphoma, but potentially other situations where [CAR T-cell therapy] is maybe circulating and causing secondary effects that we may want to mitigate. That is the greater implication that I would like to highlight here.

How should physicians monitor for secondary cancers after CAR T-cell therapy? What strategies help identify patients at high risk, and how can precision medicine be leveraged for timely intervention?

I would recommend next-generation sequencing is commonly available with several commercial panels for at least looking at mutations, and this can be done at periodic intervals, before and after [administration of CAR T-cell therapy], to look for clonal expansion in genes such as TP53 and others which have been associated with cytopenias, myelodysplastic syndrome, acute myeloid leukemia, and epigenetic modifiers such as TET2 and EZH2, which we noted in our patient.

If there is expansion of clones, then working in conjunction with lymphoma or leukemia experts to do more careful studies using [flow] cytometry or imaging as needed by the clinical scenario would be important. This will help pick up any secondary malignancy that is happening in a patient earlier and at a potentially more treatable stage.

Looking ahead, what areas of research hold the greatest potential to advance understanding and treatment in this space, and what specific questions should future studies aim to address?

Future research in this field should focus on two areas. One is the use of safer kill switches, or [CAR T-cell therapies] that can actually be modulated. As I said before, I'm a big believer [in CAR T-cell therapies], and I think [their] use is here to stay and will continue to expand. Therefore, let's all work together to make it safer. Maybe we can build [CAR Ts] that have built-in kill switches that can prevent these sort of toxicities from forming, or if they form, we can readily activate kill switches to turn them off.

The second [area] is having a deeper understanding of what the transformation mechanisms are. I mentioned some genetic mechanisms, but the entire [CAR T] process involves lymphodepletion, which create[s] an environment [that] allows cells and lymphocytes to grow at an accelerated [rate]. There's also cytokine storm, and then, as I mentioned in the case of our patient and several other cases that have been noted in literature, patients can get viral infections that can also cause cytokine stimulation.

References

1. Mount Sinai researchers pioneer first targeted therapy for rare T-cell lymphoma after CAR T treatment. News Release. Mount Sinai. Updated August 21, 2025. Accessed September 30, 2025. https://www.mountsinai.org/about/newsroom/2025/mount-sinai-researchers-pioneer-first-targeted-therapy-for-rare-t-cell-lymphoma-after-car-t-treatment
2. Aleman A, Oekelen OV, Melnekoff DT, et al. Targeted therapy of CAR+ T-cell lymphoma after anti-BCMA CAR T-cell therapy. N Engl J Med. 2025;393(8):823-825. doi:10.1056/NEJMc2504588