Targeting CCR4 in CAR-Associated Peripheral T-Cell Lymphoma

In the New England Journal of Medicine (August 2025), Aleman et al. report a case of CAR+ peripheral T-cell lymphoma (PTCL) emerging after anti-BCMA CAR-T therapy in a patient with multiple myeloma.

The malignancy presented with skin involvement and was successfully managed through a genomically informed, targeted approach. Although secondary malignancies following CAR-T are rare, this report highlights the potential for malignant T-cell evolution driven by a combination of vector integration, clonal mutations, and immune activation.

The 51-year-old male patient presented with erythematous facial lesions and lymphocytosis six months after receiving ciltacabtagene autoleucel. PET/CT imaging revealed hypermetabolic cutaneous lesions, and biopsies confirmed a double-negative (CD4⁻/CD8⁻), CAR-expressing PTCL with bone marrow infiltration. Malignant cells overexpressed CCR4, a skin-homing chemokine receptor typically associated with cutaneous T-cell lymphoma but rarely seen in PTCL, guiding a precision-based therapeutic approach.

Single-cell RNA and T-cell receptor sequencing distinguished malignant CAR+ clones from normal T-cell populations, confirming CCR4 overexpression. Functional screening of 166 FDA-approved agents identified a tumor-specific sensitivity to anthracyclines.

Based on these findings, the patient received mogamulizumab (anti-CCR4 antibody), liposomal doxorubicin, and gemcitabine, resulting in a complete remission sustained for more than 10 months. Maintenance therapy with peginterferon alfa-2a and extracorporeal photopheresis was attempted but later discontinued due to persistent cytopenias.

Genomic profiling showed plausible mechanisms of transformation. Whole-genome sequencing identified CAR vector integration into TIA1, a gene associated with tumor suppression. Immunohistochemistry confirmed loss of TIA1 expression. Heterozygous truncating mutations in TET2 and EZH2 were also detected, suggesting post-treatment clonal evolution. Transcriptomic analysis demonstrated upregulation of MYC and PI3K/AKT signaling pathways, further supporting a transformed phenotype.

The authors note that this case represents at least the second documented instance of CAR transgene integration into a known or putative tumor suppressor gene. It also highlights the utility of integrated genomic, phenotypic, and functional profiling in informing therapeutic decisions.

While the individual contributions of each treatment component cannot be determined, the clinical response supports CCR4 as a potential therapeutic target in CAR+ PTCL, particularly in cases with skin involvement.

Finally, the case underscores the importance of clinical vigilance for secondary malignancies following CAR-T therapy. The authors suggest that pre-treatment screening for clonal hematopoiesis and post-treatment surveillance may help identify patients at increased risk.

Reference

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.