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Immunotherapy Targeting HPV 16/18 Generates Potent Immune Responses in HPV- Associated Head and Neck Cancer

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Immunotherapy Targeting HPV 16/18 Generates Potent Immune Responses in HPV- Associated Head and Neck Cancer Author Manuscript Published OnlineFirst on September 21, 2018; DOI: 10.1158/1078-0432.CCR-18-1763 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Immunotherapy targeting HPV 16/18 generates potent immune responses in HPV- Associated Head and Neck Cancer Charu Aggarwal1, Roger B. Cohen1, Matthew P. Morrow2, Kimberly A. Kraynyak2, Albert J. Sylvester2, Dawson M. Knoblock2, Joshua M. Bauml1, Gregory S. Weinstein3, Alexander Lin4, Jean Boyer2, Lindsay Sakata2, Sophie Tan2, Aubrey Anton2, Kelsie Dickerson2, Drishty Mangrolia2, Russell Vang5, Michael Dallas2, Sandra Oyola2, Susan Duff2, Mark Esser6, Rakesh Kumar6, David Weiner7, Ildiko Csiki2 and Mark L. Bagarazzi2 1 Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA 2 Inovio Pharmaceuticals, Inc. Plymouth Meeting, PA, USA 3 Department of Otorhinolaryngology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA 4 Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA 5 Johns Hopkins University, Baltimore, MD, USA 6 MedImmune, Gaithersburg, MD, USA 7 Wistar Institute, Philadelphia, PA, USA Running Title: DNA immunotherapy in HPV-associated Head and Neck Cancer Keywords: Immunotherapy, HPV, Head and Neck Cancer, Combination immunotherapy, Oropharyngeal carcinoma Word Count: 5662 Number of Tables: 1 Number of Figures: 5 Corresponding Author: Charu Aggarwal, MD, MPH, Assistant Professor, Department of Medicine, Hematology-Oncology Division, University of Pennsylvania, 10-137, South Pavilion, 3400 Civic Center Boulevard, Philadelphia, PA 19104. Email: [email protected]. Phone 215-662-6318, Fax: 215-349-5326 Conflict of Interest Disclosures: Charu Aggarwal reported consulting or advisory roles with Genentech, Bristol-Myers Squibb, Lilly, and Celgene; and institutional research funding from Genetech/Roche, Incyte, Macrogenics, and Merck Sharp & Dohme. Roger B. Cohen reported honoraria from Bristol-Myers Squibb; a consulting or advisory role with Heat Biologics, Takeda, Cerulean Pharma, Kolltan Pharmacueticals, Zymeworks, and Pfizer; institutional research funding from Heat Biologics, Macrogenetics, Merck, Takeda, Cleave Biosciences, and Celldex; and travel, accommodations, or expenses from Heat Biologics, Takeda, Kolltan Pharmaceuticals, Cerulean Pharma, Zymeworks, Bristol-Meyers Squibb, and Pfizer. J.M. Bauml reported consulting or advisory roles with Clovis Oncology, Bristol-Myers Squibb, Merck, AstraZeneca, Genentech, Celgene, Boehringer Ingelheim, and Guardant Health; and institutional research funding from Merck, Carevive Systems, Novartis, Incyte, Bayer, and Janssen. GS Weinstein and 1 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 21, 2018; DOI: 10.1158/1078-0432.CCR-18-1763 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Alexander Lin have no relevant disclosures. Russell Vang has no relevant disclosures. David B. Weiner received a SRA research grant from Inovio Pharmaceuticals, has received speakers honoraria from Inovio Pharmaceuticals, GeneOne, Astrazeneca, BMGF, he has ownership interest (including patents) in Inovio Pharmaceuticals and is a consultant/advisory board member for Inovio Pharmaceuticals, a consultant for GeneOne and Astrazeneca and Merck. All authors whose listed association is Inovio Pharmaceuticals (MPM, KAK, AJS, DMK, JB, LS, ST, AA, KD, DM, MD, SO, SD, IC, MLB) and Medimmune (ME, RK) are employees of that entity, own stock or stock options relative to that entity and may own one or more patents relating to the drugs being described in this publication. Funding: Supported by NCI P30 Cancer Center Support Grant # 5-P30-CA-016520-38 2 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 21, 2018; DOI: 10.1158/1078-0432.CCR-18-1763 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 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. Experimental Design: We report Phase Ib/II safety, tolerability and immunogenicity results of immunotherapy with MEDI0457 (DNA immunotherapy targeting HPV16/18 E6/E7 with IL-12 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 (AEs). Eighteen of 21 evaluable patients showed elevated antigen specific T cell activity by IFN ELISpot and persistent cellular responses surpassing 100 SFU/106 PBMC were noted out to one year. Induction of HPV-specific CD8+ T cells was observed. MEDI0457 shifted the CD8+/FoxP3+ ratio in 4/5 post-immunotherapy tumor samples and increased the number of perforin+ immune infiltrates in all five 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%). 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. Statement of translational relevance Human Papilloma Virus (HPV) associated Head and Neck Cancer (HNSCCa) is an emerging global epidemic, where despite the availability of highly curative treatments, some patients will eventually develop recurrent and/or metastatic disease. The availability of checkpoint inhibitors 3 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 21, 2018; DOI: 10.1158/1078-0432.CCR-18-1763 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. for metastatic HNSCCa has changed the outcomes for this disease but durable benefit and survival gains occur only in a subset of patients (~15-20%). Tumor HPV status does not seem to be a principal driver of outcomes with PD-1 directed therapies. An approach targeting HPV- specific “non-self” antigens to activate the immune system represents a potential mechanism to improve outcomes. This clinical trial demonstrates that a DNA immunotherapeutic agent targeting HPV 16/18 E6/E7 is safe, with promising antigen-specific immune activation in patients with HNSCCa. Our findings suggest that HPV viral neoantigens can be therapeutically targeted as a complementary immune strategy to PD-1/PD-L1 inhibition in HPV-associated HNSCCa to improve patient outcomes. Introduction Squamous cell carcinoma of the head and neck (HNSCCa) is diagnosed in over 500,000 patients worldwide each year, accounting for 5% of all malignancies (1). The immune system plays an important role in head and neck carcinogenesis. Even though HNSCCa in general are among the most highly immune-infiltrated cancer types, certain subsets of HNSCCa are characterized by an immunosuppressive environment, marked by T cell dysfunction, low levels of CD4+ and CD8+ T cells, increased T-regulatory cells (Tregs), cytokine alterations and antigen presentation defects (2-4). Oncogenic human papilloma virus (HPV) infection accounts for a significant number of HNSCCa, most of which are related to the HPV 16 subtype (5, 6). HPV-associated HNSCCa may be particularly dependent on aberrant immune checkpoints that create an immune- privileged site for HPV infection and function as an adaptive resistance mechanism of tumor against host (7, 8). The availability of checkpoint inhibitors for metastatic HNSCCa has changed outcomes for this disease (9-12) but durable benefit and survival gains occur only in a subset of patients (~15- 20%). Tumor HPV status does not seem to be a principal driver of outcome with this new therapy (13, 14). Combination strategies may increase the percentage of patients that respond to PD-1 immunotherapy (15, 16). One such potential approach is the addition of HPV-specific immunotherapy, targeting HPV-specific “non-self” antigens to activate the immune system to 4 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 21, 2018; DOI: 10.1158/1078-0432.CCR-18-1763 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. recognize the cancer. The HPV E6 and E7 oncoproteins represent ideal targets for an immunotherapeutic agent because of their constitutive expression in HPV-associated tumors and their crucial role in the induction and maintenance of HPV-associated disease (17). HPV-specific immunotherapymay eliminate preexisting
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