Immunotherapy targeting HPV 16/18 generates potent immune responses in HPV-Associated Head and Neck Cancer.
CLINICAL CANCER RESEARCH(2019)
Abstract
Purpose: Clinical responses with programmed death (PD-1) receptor-directed antibodies occur in about 20% of patients with advanced head and neck squamous cell cancer (HNSCCa). Viral neoantigens, such as the E6/E7 proteins of HPV16/18, are attractive targets for therapeutic immunization and offer an immune activation strategy that may be complementary to PD-1 inhibition. Patients and Methods: We report phase Ib/II safety, tolerability, and immunogenicity results of immunotherapy with MEDI0457 (DNA immunotherapy targeting HPV16/18 E6/E7 with IL12 encoding plasmids) delivered by electroporation with CELLECTRA constant current device. Twenty-two patients with locally advanced, p16(+) HNSCCa received MEDI0457. Results: MEDI0457 was associated with mild injection site reactions, but no treatment-related grade 3-5 adverse events (AE) were noted. Eighteen of 21 evaluable patients showed elevated antigen-specific T-cell activity by IFN gamma ELISpot, and persistent cellular responses surpassing 100 spot-forming units (SFUs)/10(6) peripheral blood mononuclear cells (PBMCs) were noted out to 1 year. Induction of HPV-specific CD8(+) T cells was observed. MEDI0457 shifted the CD8(+) /FoxP3(+) ratio in 4 of 5 post immunotherapy tumor samples and increased the number of perforin (+) immune infiltrates in all 5 patients. One patient developed metastatic disease and was treated with antiPD-1 therapy with a rapid and durable complete response. Flow-cytometric analyses revealed induction of HPV16-specific PD-1(+) CD8(+) T cells that were not found prior to MEDI0547 (0% vs. 1.8%). Conclusions: These data demonstrate that MEDI0457 can generate durable HPV16/18 antigen-specific peripheral and tumor immune responses. This approach may be used as a complementary strategy to PD-1/PD-L1 inhibition in HPV-associated HNSCCa to improve therapeutic outcomes.
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Key words
immunotherapy,potent immune responses,head,hpv-associated
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