Tre-O2-04 - Mogamulizumab induces long term immune restoration and reshapes tumoral heterogeneity in Sézary syndrome

Abstract

Mogamulizumab, an anti-CCR4 monoclonal antibody, has shown to increase progression-free survival in cutaneous T-cell lymphoma. We hypothesized that, besides the targeted depletion of Sézary cells (SCs), mogamulizumab may contribute to immunological changes, improving clinical response. We also explored potential phenotypic changes of SCs during treatment, potentially resulting in resistance/tumor escape to therapy. We have prospectively followed 26 SS patients with B2 stage before mogamulizumab initiation. We performed extended phenotypic characterization of malignant and benign compartments, using KIR3DL2, TCRVb and/or CD26 markers, every month, up to one year. Prior to mogamulizumab, the non-malignant (benign) subset of CD4+ T-cells displayed exhausted phenotypes. When comparing SCs, benign and controls CD4+ T cells, our data showed a gradient of PD1, TIGIT, DNAM, CD27, CD28 and CD70 expression. All patients presented SCs with heterogeneous surface phenotypes and differential expression of individual markers were found within distinct malignant subsets. An early complete blood response was observed in 17/26 patients and was associated to a higher baseline CCR4 expression on SCs. A drastic decrease in benign T-cells and activated Treg absolute counts was observed during the first 4 weeks. Long-term follow-up revealed the emergence of an immune restoration involving CD8+ and naive and TSCM CD4+ subsets, concomitant with almost complete disappearance of exhausted T lymphocytes. Finally, the development of resistance/tumor escape to mogamulizumab therapy allowed us to longitudinally follow phenotypic characteristics of SCs and revealed the emergence of CCR4–SCs displaying significant changes in their heterogeneity patterns. In conclusion, mogamulizumab is not only aimed at eradicating malignant-cells but is likely contributing to the restoration of an efficient immunity. This is of importance as a competent immune status is required for effective anti-infectious and anti-tumoral responses as well as for the efficacy of further immunotherapies.