Immunomodulation to enhance the efficacy of an HPV therapeutic vaccine

• Published in: Journal for immunotherapy of cancer Vol. 8; no. 1; p. e000612
• Main Authors: Smalley Rumfield, Claire, Pellom, Samuel T, Morillon II, Y Maurice, Schlom, Jeffrey, Jochems, Caroline
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group LTD 17-06-2020; BMJ Publishing Group
• Series: Original research
• Subjects: Antibodies; Antigens; Apoptosis; Cancer; Cancer therapies; Cervical cancer; Clinical trials; Clinical/Translational Cancer Immunotherapy; Genital cancers; Head & neck cancer; Human papillomavirus; Immunotherapy; Infections; Laboratory animals; Lipids; Lymphocytes; Patients; Peptides; Proteins; R&D; Research & development; Response rates; Tumors; Vaccines; United States > US; Maryland
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2020-000612

BackgroundWhile prophylactic human papillomavirus (HPV) vaccines will certainly reduce the incidence of HPV-associated cancers, these malignancies remain a major health issue. PDS0101 is a liposomal-based HPV therapeutic vaccine consisting of the immune activating cationic lipid R-DOTAP and HLA-unrestricted HPV16 peptides that has shown in vivo CD8+ T cell induction and safety in a phase I study. In this report, we have employed the PDS0101 vaccine with two immune modulators previously characterized in preclinical studies and which are currently in phase II clinical trials. Bintrafusp alfa (M7824) is a first-in-class bifunctional fusion protein composed of the extracellular domains of the transforming growth factor-β receptor type II (TGFβRII) fused to a human IgG1 monoclonal antibody blocking programmed cell death protein-1 ligand (PDL1), designed both as a checkpoint inhibitor and to bring the TGFβRII ‘trap’ to the tumor microenvironment (TME). NHS-interleukin-12 (NHS-IL12) is a tumor targeting immunocytokine designed to bring IL-12 to the TME and thus enhance the inflammatory Th1 response.MethodsWe employed TC-1 carcinoma (expressing HPV16 E6 and E7 and devoid of PDL1 expression) in a syngeneic mouse model in monotherapy and combination therapy studies to analyze antitumor effects and changes in immune cell types in the spleen and the TME.ResultsAs a monotherapy, the PDS0101 vaccine generated HPV-specific T cells and antitumor activity in mice bearing HPV-expressing mEER oropharyngeal and TC-1 lung carcinomas. When used as a monotherapy in the TC-1 model, NHS-IL12 elicited antitumor effects as well as an increase in CD8+ T cells in the TME. When used as a monotherapy, bintrafusp alfa did not elicit antitumor effects or any increase in T cells in the TME. When all three agents were used in combination, maximum antitumor effects were observed, which correlated with increases in T cells and T-cell clonality in the TME.ConclusionThese studies provide the rationale for the potential clinical use of combinations of agents that can (1) induce tumor-associated T-cell responses, (2) potentiate immune responses in the TME and (3) reduce immunosuppressive entities in the TME.