Successful treatment of mogamulizumab‐resistant mycosis fungoides with mogamulizumab plus etoposide combined therapy: Investigation of the immunomodulatory effects of etoposide on the tumor microenvironment

Abstract

Mogamulizumab shows cytotoxicity against CCR4+ lymphoma cells by antibody‐dependent cell‐mediated cytotoxicity (ADCC) in advanced cutaneous T‐cell lymphoma (CTCL) patients. Although mogamulizumab is used as one of the anchor drugs for the treatment of advanced CTCL, its efficacy is unsatisfactory, especially in mycosis fungoides (MF). Therefore, additional drugs to enhance the antitumor effects of mogamulizumab are needed to further optimize its use for the treatment of MF. In this report, two cases of mogamulizumab‐resistant MF successfully treated with additional administration of etoposide are presented. Moreover, the possible mechanisms of mogamulizumab‐etoposide combined therapy for the treatment of MF were investigated based on the modulation of chemokine profiles in vivo using an EL‐4 mouse T‐cell lymphoma model. Intraperitoneal administration of etoposide significantly increased the mRNA expressions of CCL17, CXCL5, and CXCL10, suggesting that CCR4+ CTCL cells gather around the tumor‐associated macrophagess. Furthermore, the immunomodulatory effects of etoposide on the mRNA expressions of these chemokines were validated using monocyte‐derived M2 macrophages in vitro. Since mogamulizumab shows cytotoxicity against CCR4+ lymphoma cells by ADCC that depends on the contact between the lymphoma cells and the effector cells, these chemokines could enhance the therapeutic effect of mogamulizumab.

Successful treatment of CCR4 + mycosis fungoides palmaris et plantaris with mogamulizumab monotherapy

“…anchor drugs for advanced CTCL. [5][6][7] Since our present case highly expressed CCR4, located at superficial dermis to subcutaneous tissue and marginal skin is unclear, we selected mogamulizumab monotherapy, which achieved complete remission of the skin lesions. In addition, since the serum levels of CCL22 decreased in parallel with the disease activity, CCL22 might not only be a biomarker for bexarotene monotherapy, 3 but also a biomarker to evaluate the efficacy of mogamulizumab.…”

“…Notably, we evaluated another chemokine, CCL19 (ligand for CCR7) and CXCL10 (Th1/ Th17 chemokines) before and after the administration of mogamulizumab, suggesting that mogamulizumab selectively decreased the serum level of CCL22. In other words, mogamulizumab might induce an anti-tumor immune response against CCR4+ CTCL not only by its ADCC, but also effect the chemokine profiles to modulate the tumor microenvironment like other anti-CTCL drugs such as bexarotene, 3 etoposide, 7 and interferons. 8 Since we presented a single case, further cases are needed to gain additional insight into the pathomechanisms of MFPP in patients treated with mogamulizumab.…”

Topical and Systemic Formulation Options for Cutaneous T Cell Lymphomas

“…Since the ORR of mogamulizumab monotherapy for relapsed CTCL is 28%, several mogamulizumab-based combination therapies have been reported recently [27][28][29][30]. For example, the combined administration of etoposide and mogamulizumab was shown to be useful for the treatment of mogamulizumab-resistant MF [28,29].…”

“…Since the ORR of mogamulizumab monotherapy for relapsed CTCL is 28%, several mogamulizumab-based combination therapies have been reported recently [27][28][29][30]. For example, the combined administration of etoposide and mogamulizumab was shown to be useful for the treatment of mogamulizumab-resistant MF [28,29]. Notably, using an in vivo model (EL4 mouse lymphoma model), the intraperitoneal administration of etoposide significantly increased the expression in implanted tumors of mRNAs encoding CCL17, CXCL5, and CXCL10 [28].…”

“…For example, the combined administration of etoposide and mogamulizumab was shown to be useful for the treatment of mogamulizumab-resistant MF [28,29]. Notably, using an in vivo model (EL4 mouse lymphoma model), the intraperitoneal administration of etoposide significantly increased the expression in implanted tumors of mRNAs encoding CCL17, CXCL5, and CXCL10 [28]. Those researchers concluded that CCR4+ CTCL cells, as well as CXCR3+ effector cells and CXCR2+ monocytes, accumulate in tumor sites, leading to potentiation of the ADCC activities of mogamulizumab [28].…”