Introduction: Mogamulizumab, a CC chemokine receptor 4 (CCR4)-targeting antibody, is approved for relapsed/refractory mycosis fungoides/Sézary syndrome (MF/SS) following ≥1 systemic therapy. In a Phase 2 trial assessing a novel 2.0 mg/kg every-4-week dosing regimen (NCT04745234), immunologic and transcriptomic changes associated with efficacy and toxicities were assessed to potentially predict outcomes and better understand disease biology.
Methods: Immunohistochemistry (IHC), transcriptomic profiling (custom 825-gene IO360+CTCL panel), and HLA gene analyses on paired pre- and post-treatment skin biopsies, including both involved and uninvolved skin and drug eruption (DE) lesions, and blood samples were assessed.
Results: In skin, IHC showed CCR4⁺/FoxP3⁺ Tregs decreased and CD8⁺/CD163⁺ cytotoxic immune cell infiltration increased after treatment. Gene expression profiling demonstrated inter- and intra-patient heterogeneity. Post-treatment samples showed Treg and CCR4 downregulation, IFN-γ signaling upregulation, cytotoxic activation, and dendritic cell expansion in responders. DE samples' transcriptomic profile indicated a macrophage shift toward an inflammatory phenotype. Baseline HLA genotyping showed responders with higher total mutation burden (SNPs and Indels) and greater intra-allelic heterogeneity, whereas non-responders showed a more homogenous allelic profile. Patients who developed DEs also exhibited elevated baseline mutation burden, but with reduced intra-allelic variations. Several baseline SNPs were associated with both treatment response and DE phenotype.
Conclusions: Mogamulizumab induced dynamic reprogramming of the tumor microenvironment, including enhanced immune effector cell infiltration, and specific genomic and HLA profiles associated with clinical response. These data support a model in which mogamulizumab-mediated Treg clearance unlocks.
Abstract and data originally presented at EORTC-CLTG 2025.
