Merkel cell polyomavirus-specific immune responses in patients with Merkel cell carcinoma receiving anti-PD-1 therapy

Miller N, Church C, Fling S, Kulikauskas R, Ramchurren N, Shinohara M, Kluger H, Bhatia S, Lundgren L, Cheever M, Topalian S, Nghiem P

J Immunother Cancer. 2018 Nov 27;6(1):131. doi: 10.1186/s40425-018-0450-7.

PMID: 30482247

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Background: Merkel cell carcinoma (MCC) is an aggressive skin cancer that frequently responds to anti-PD-1 therapy. MCC is associated with sun exposure and, in 80% of cases, Merkel cell polyomavirus (MCPyV). MCPyVspecific T and B cell responses provide a unique opportunity to study cancer-specific immunity throughout PD-1 blockade therapy.

Methods: Immune responses were assessed in patients (n = 26) with advanced MCC receiving pembrolizumab. Peripheral blood mononuclear cells (PBMC) were collected at baseline and throughout treatment. MCPyVoncoprotein antibodies were quantified and T cells were assessed for MCPyV-specificity via tetramer staining and/or cytokine secretion. Pre-treatment tumor biopsies were analyzed for T cell receptor clonality.

Results: MCPyV oncoprotein antibodies were detectable in 15 of 17 (88%) of virus-positive MCC (VP-MCC) patients. Antibodies decreased in 10 of 11 (91%) patients with responding tumors. Virus-specific T cells decreased over time in patients who had a complete response, and increased in patients who had persistent disease. Tumors that were MCPyV(+) had a strikingly more clonal (less diverse) intratumoral TCR repertoire than virus-negative tumors (p = 0.0001).

Conclusions: Cancer-specific T and B cell responses generally track with disease burden during PD-1 blockade, in proportion to presence of antigen. Intratumoral TCR clonality was significantly greater in VP-MCC than VN-MCC tumors, suggesting expansion of a limited number of dominant clones in response to fewer immunogenic MCPyV antigens. In contrast, VN-MCC tumors had lower clonality, suggesting a diverse T cell response to numerous neoantigens. These findings reveal differences in tumor-specific immunity for VP-MCC and VN-MCC, both of which often respond to anti- PD-1 therapy.

Keywords: Merkel cell carcinoma, Merkel cell polyomavirus, Viral cancer antigen, Immunotherapy, Pembrolizumab,
Anti-PD-1, T cell

J Immunother Cancer. 2018 Nov 27;6(1):131. doi: 10.1186/s40425-018-0450-7.