Mechanisms of Resistance to Anti-CCR4 Antibody, Mogamulizumab, in Cutaneous T cell Lymphoma
Oral presentation
Mogamulizumab (Moga), a monoclonal humanized anti-CCR4 antibody, is an effective and well-tolerated treatment for patients with mycosis fungoides and Sézary syndrome. Despite almost universal expression of CCR4 in CTCL, most patients will eventually develop resistance to moga. The mechanisms of resistance to mogamulizumab have not been characterized. An understanding of the resistance mechanisms will shed light on the disease biology and inform selection of next line therapies and the development of future CCR4-directed treatments.
We identified 19 patients with mycosis fungoides or Sézary syndrome in whom mogamulizumab had been discontinued due to disease progression. Seven patients had developed resistance after an initial period of response, while 12 patients were refractory to therapy. We performed immune phenotyping and targeted next generation sequencing at the time of disease progression.
We identified loss of CCR4 expression by immunohistochemistry and flow cytometry in 8 patients post treatment. Three patients were found to harbor previously undescribed, emergent CCR4 mutations targeting the N-terminal and transmembrane domains at the time of disease progression. Emerging CCR4 copy number loss was detected in 2 patients concurrent with CCR4 mutations. Acquisition of CCR4 genomic alterations corresponded with loss of CCR4 expression by immunohistochemistry.
In conclusion, our study indicates that resistance to mogamulizumab in CTCL is frequently associated with loss of CCR4 expression and the emergence of CCR4 genomic alterations. This finding has important implications for management and monitoring of CTCL patients on mogamulizumab and the development of CCR4 therapies in cutaneous T-cell lymphomas.
We identified 19 patients with mycosis fungoides or Sézary syndrome in whom mogamulizumab had been discontinued due to disease progression. Seven patients had developed resistance after an initial period of response, while 12 patients were refractory to therapy. We performed immune phenotyping and targeted next generation sequencing at the time of disease progression.
We identified loss of CCR4 expression by immunohistochemistry and flow cytometry in 8 patients post treatment. Three patients were found to harbor previously undescribed, emergent CCR4 mutations targeting the N-terminal and transmembrane domains at the time of disease progression. Emerging CCR4 copy number loss was detected in 2 patients concurrent with CCR4 mutations. Acquisition of CCR4 genomic alterations corresponded with loss of CCR4 expression by immunohistochemistry.
In conclusion, our study indicates that resistance to mogamulizumab in CTCL is frequently associated with loss of CCR4 expression and the emergence of CCR4 genomic alterations. This finding has important implications for management and monitoring of CTCL patients on mogamulizumab and the development of CCR4 therapies in cutaneous T-cell lymphomas.