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Aggarwal, Charu; Cohen, Roger B; Morrow, Matthew P; Kraynyak, Kimberly A; Sylvester, Albert J; Knoblock, Dawson M; Bauml, Joshua M; Weinstein, Gregory S; Lin, Alexander; Boyer, Jean; Sakata, Lindsay; Tan, Sophie; Anton, Aubrey; Dickerson, Kelsie; Mangrolia, Drishty; Vang, Russell; Dallas, Michael; Oyola, Sandra; Duff, Susan; Esser, Mark; Kumar, Rakesh; Weiner, David; Csiki, Ildiko; Bagarazzi, Mark L
Clinical cancer research, 01/2019, Letnik: 25, Številka: 1Journal Article
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. 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. 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 IFNγ ELISpot, and persistent cellular responses surpassing 100 spot-forming units (SFUs)/10 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 anti-PD-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%). 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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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Vir: Osebne bibliografije
in: SICRIS
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