The use of a targeted therapy–based combination, comprising mogamulizumab-kpkc (Poteligeo), liposomal doxorubicin, and gemcitabine, produced a complete remission (CR) in a patient with CAR-positive peripheral T-cell lymphoma (PTCL) who previously received BCMA-directed CAR T-cell therapy in the form of ciltacabtagene autoleucel (cilta-cel; Carvykti) for multiple myeloma, according to findings from a case study published in The New England Journal of Medicine.1,2
The report from Samir Parekh, MD, Adolfo Aleman, PhD, and Oliver Van Oekelen, MD, PhD, and colleagues from Mount Sinai in New York, New York, also explained that the 51-year-old male patient discontinued treatment after achieving CR, and he subsequently received maintenance therapy with pegylated interferon alfa-2a (Pegasys) and extracorporeal photochemotherapy; however, maintenance was discontinued after approximately 2 months due to persistent cytopenia. The remission was ongoing with more than 10 months of follow-up.
“Although the molecular data supported CCR4 targeting, the individual contribution of each component of our treatment regimen cannot be determined without prospective validation,” study authors noted in the publication. “However, our studies identify CCR4 as a possible target for CAR-related toxic effects, including peripheral T-cell lymphoma, particularly in cases with skin involvement.”
Why Was CCR4 Identified as a Potential Target in this CAR-positive PCTL Case Study?
Study authors underscored the rarity of the emergence of secondary malignancies—including CAR-positive T-cell lymphomas—after CAR T-cell therapy, as effective management of these cancers remains undefined.
In this patient with CAR-positive PTCL, erythematous facial lesions and lymphocytosis developed 6 months following the administration of cilta-cel, and the patient’s skin involvement was associated with CCR4 overexpression. Notably, CCR4, which is a skin-homing chemokine receptor, is generally expressed in patients with cutaneous T-cell lymphomas. However, it is rarely overexpressed in patients with PTCL, and its expression may be associated with poor outcomes.
After skin and bone marrow biopsies confirmed a diagnosis of CAR-positive, CD4- and CD8-negative PTCL, clinicians performed multimodal characterization via single-cell RNA and T-cell receptor sequencing, which served to distinguish malignant from healthy T cells. This process also identified the high expression of CCR4, which was subsequently validated by flow cytometry.
Clinicians then performed an ex vivo screen of 166 drugs that have been approved by the FDA, which revealed that the tumor was sensitive to anthracycline-based treatment. This, along with the CCR4 overexpression, informed treatment with mogamulizumab in combination with liposomal doxorubicin, and gemcitabine.
What Did Whole-Genome Sequencing Reveal for this Patient With CAR-Positive PTCL?
Investigators further characterized the molecular profile of the tumor by conducting whole-genome sequencing, which revealed CAR vector integration within intron 7 of TIA1, along with the absence of TIA1 expression, per immunohistochemistry.
“This represents at least the second case of insertion into a known or putative tumor suppressor gene. Additional heterozygous truncating mutations in TET2 and EZH2, which were absent in pre-CAR T-cell samples, were also identified,” study authors wrote. “These mutations are frequently associated with clonal hematopoiesis and T-cell lymphomas and may have contributed to malignant transformation.”
Furthermore, RNA sequencing showed that the MYC and PI3K/AKT signaling pathways were both upregulated.
What Does This Case Study Mean for CAR T-Cell Therapy and Secondary Malignancies?
Study authors concluded by explaining that awareness of the risk of secondary malignancies following CAR T-cell therapy remains paramount, suggesting that screening for clonal hematopoiesis before the administration of CAR T-cell therapy, along with monitoring after infusion, could help identify patients at higher risk of developing a subsequent malignancy.
Future work should dissect the interplay of vector integration, acquired genetic and epigenetic lesions, cytokine-driven proliferation, and serial infections in driving T-cell transformation and lymphomagenesis,” study authors concluded. “We have shown that treatment based on genomic, phenotypic, and functional profiling can provide an effective therapeutic strategy in these rare but serious cases.”
References
- Aleman A, Van Oekelen O, 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
- Mount Sinai researchers pioneer first targeted therapy for rare T-cell lymphoma after CAR T treatment. News Release. Mount Sinai. August 21, 2025. Accessed October 3, 2025. https://www.mountsinai.org/about/newsroom/2025/mount-sinai-researchers-pioneer-first-targeted-therapy-for-rare-t-cell-lymphoma-after-car-t-treatment