A novel mouse model of cutaneous T‐cell lymphoma revealed the combined effect of mogamulizumab with psoralen and ultraviolet a therapy

Abstract

Mycosis fungoides (MF) is a subtype of cutaneous T‐cell lymphoma (CTCL). Topical or systemic treatment with psoralen, such as 8‐methoxypsoralen (8‐MOP), followed by ultraviolet A (UVA) irradiation (PUVA therapy) is an effective phototherapy for early‐stage MF. However, the efficacy of PUVA therapy for advanced‐stage MF is not satisfactory, and the ideal combination partner for PUVA therapy has not yet been found. In this study, we developed a new mouse model of CTCL in which efficacy of PUVA was detected and further evaluated the efficacy of combination treatment of PUVA and mogamulizumab, an anti‐CCR4 monoclonal antibody. Cytotoxicity of PUVA therapy against HH cells, a CTCL cell line, was observed in vitro. The cytotoxicity was dependent on both 8‐MOP and UVA. Using HH cells, we developed a mouse model in which HH cells were subcutaneously inoculated in the ear. In this model, PUVA therapy suppressed tumour growth with statistical significance, while 8‐MOP or UVA alone did not. Combination therapy of PUVA and mogamulizumab showed greater antitumor activity than either monotherapy with statistical significance. In the histological analysis of the tumour tissue, PUVA accelerated tumour necrosis and then induced the infiltration inflammatory cells in the necrotic area, suggesting that these cells served as effector cells for mogamulizumab. This combination therapy is expected to be a beneficial option for CTCL therapy.

Development of Bexarotene Analogs for Treating Cutaneous T-Cell Lymphomas

“…Most notably, analogs A75-A77 demonstrated an enhanced ability to induce RXR homodimerization (Figure 2B), activate RXRE (Figure 3B), and reduce CTCL cell proliferation (Figure 4) relative to bexarotene. The results suggest that these compounds, if tested with in vivo CTCL animal models [40][41][42][43][44], may produce more satisfactory outcomes in CTCL disease remission. However, A77 was cytotoxic at the lowest concentration evaluated, so additional testing is warranted before moving onto a mouse model.…”

“Next top” mouse models advancing CTCL research

“…The “nude” (nu/nu) mouse model, which lacks a mature thymus due to a Foxn1 gene mutation, resulting in underdeveloped T cells ( Kaushik et al, 1995 ), has become a critical model for evaluating CTCL therapies, especially in terms of treatment responses for MF patient-derived skin lesions. These mice with transplants of MF have shown superior responses to combination therapies like PUVA and mogamulizumab, a monoclonal antibody targeting CCR4, compared to monotherapies ( Thaler et al, 2004 ; Nakahashi et al, 2022 ). Studies using “nude” mice highlight the potential of Vorinostat and the HIF-1α inhibitor Echinomycin in CTCL management ( Wang et al, 2020 ; Xia et al, 2020 ).…”

Targeting the deubiquitinase USP2 for malignant tumor therapy (Review)

“…Cutaneous T-cell lymphoma (CTCL) is caused by the clonal proliferation of T lymphocytes originating in the skin and is a type of extranodal non-Hodgkin lymphoma. Psoralen with ultraviolet A (PUVA) phototherapy is a common treatment strategy for CTCL in clinical settings ( 145 , 146 ). A study demonstrated that USP2 is expressed in both quiescent and activated T lymphocytes, and its expression is significantly reduced in advanced CTCL.…”