Resistance to Mogamulizumab Is Associated with Loss of CCR4 in Cutaneous T Cell Lymphoma
Authors: Beygi Sara , Fernandez-Pol Sebastian , Duran George , Kim Youn H. , Khodadoust Michael S. 
Published: November 2021

Abstract
Background: Mogamulizumab is a humanized anti-CCR4 antibody approved for the treatment of mycosis fungoides and Sézary Syndrome. Despite almost universal expression of CCR4 in these diseases, many patients eventually develop resistance to mogamulizumab (moga). The mechanisms of resistance to moga 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 for patients with cutaneous T cell lymphoma (CTCL).
Methods: We identified 19 patients with mycosis fungoides or Sezary syndrome in whom moga had been discontinued due to lack or loss of response to therapy. Archival blood and skin and/or lymph node biopsies after discontinuation of treatment were studied. Specimens collected prior to initiation of moga were also procured whenever available. CCR4 protein expression was determined by immunohistochemistry (IHC; clone L291H4; Biolegend). Targeted sequencing was performed using the Agilent XTHS2 platform (Agilent) with a custom Agilent SureSelect panel that included full coverage of the exonic regions of CCR4.
Results:
Fourteen patients had Sézary syndrome and five had mycosis fungoides. Twelve patients were classified as primary refractory to treatment and the remaining seven patients had secondary resistance. Median duration of treatment with moga was 3.5 months (range: 2-41). CCR4 expression was non-detectable in post-treatment specimens of 8 of 14 (57%) patients with evaluable specimens. Targeted DNA sequencing of post-treatment samples revealed novel coding mutations of CCR4 in three patients. Only one of the 3 mutations (L21V) overlapped with the known N-terminal mogamulizumab binding epitope. The other two mutations occurred in transmembrane domains (M116R, T161-W162 delinsSR). Two patients with mutations in CCR4 also had unequivocal copy number loss involving the CCR4 locus. Acquisition of CCR4 genomic alterations corresponded with lack of CCR4 expression by immunohistochemistry. In-vitro validation of the novel CCR4 mutations is ongoing and results from these experiments will be included in the final presentation.
Conclusion: Overall our study indicates that potential loss of CCR4 expression, with or without underlying genomic aberrations, represents a major hurdle in the development of future CCR4 targeting strategies in CTCL. This finding has important implications for management and monitoring of cutaneous T cell lymphoma patients receiving CCR4 directed therapies.

Disclosures
Beygi: Kite/Gilead: Current Employment. Kim: Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CRISPR: Research Funding; Eisai: Research Funding; Soligenix: Research Funding; Portola: Membership on an entity's Board of Directors or advisory committees, Research Funding; Elorac: Research Funding; Galderma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; Corvus: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Kirin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Secura Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion, AstraZeneca Rare Disease: Other: Study investigator; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon: Research Funding. Khodadoust: Alexion, AstraZeneca Rare Disease: Other: Study investigator; Myeloid Therapeutics: Membership on an entity's Board of Directors or advisory committees; CRISPR Therapeutics, Nutcracker Therapeutics: Research Funding.