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Characterization of recombinant gorilla adenovirus HPV therapeutic vaccine PRGN-2009
Samuel T. Pellom, … , Jeffrey Schlom, Caroline Jochems
Samuel T. Pellom, … , Jeffrey Schlom, Caroline Jochems
Published March 2, 2021
Citation Information: JCI Insight. 2021;6(7):e141912. https://doi.org/10.1172/jci.insight.141912.
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Research Article Immunology Oncology

Characterization of recombinant gorilla adenovirus HPV therapeutic vaccine PRGN-2009

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Abstract

There are approximately 44,000 cases of human papillomavirus–associated (HPV-associated) cancer each year in the United States, most commonly caused by HPV types 16 and 18. Prophylactic vaccines successfully prevent healthy people from acquiring HPV infections via HPV-specific antibodies. In order to treat established HPV-associated malignancies, however, new therapies are necessary. Multiple recombinant gorilla adenovirus HPV vaccine constructs were evaluated in NSG-β2m–/– peripheral blood mononuclear cell–humanized mice bearing SiHa, a human HPV16+ cervical tumor, and/or in the syngeneic HPV16+ TC-1 model. PRGN-2009 is a therapeutic gorilla adenovirus HPV vaccine containing multiple cytotoxic T cell epitopes of the viral oncoproteins HPV 16/18 E6 and E7, including T cell enhancer agonist epitopes. PRGN-2009 treatment reduced tumor volume and increased CD8+ and CD4+ T cells in the tumor microenvironment of humanized mice bearing the human cervical tumor SiHa. PRGN-2009 monotherapy in the syngeneic TC-1 model also reduced tumor volumes and weights, generated high levels of HPV16 E6–specific T cells, and increased multifunctional CD8+ and CD4+ T cells in the tumor microenvironment. These studies provide the first evaluation to our knowledge of a therapeutic gorilla adenovirus HPV vaccine, PRGN-2009, showing promising preclinical antitumor efficacy and induction of HPV-specific T cells, along with the rationale for its evaluation in clinical trials.

Authors

Samuel T. Pellom, Claire Smalley Rumfield, Y. Maurice Morillon II, Nicholas Roller, Lisa K. Poppe, Douglas E. Brough, Helen Sabzevari, Jeffrey Schlom, Caroline Jochems

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Figure 5

HPV-specific T cells in the TME and periphery induced by PRGN-2009.

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HPV-specific T cells in the TME and periphery induced by PRGN-2009.
C57B...
C57BL/6 mice (n = 6–7 per group) bearing s.c. TC-1 HPV16+ tumors were treated with empty vector control (1 × 109 VP, s.c.) or PRGN-2009 (1 × 109 VP, s.c.) on days 7 and 14 after tumor implantation. At the end of study (day 23), tumors were harvested. CD45+ TILs were isolated and stimulated overnight in triplicate wells with combined overlapping HPV16 E6/E7 15-mer peptides or DMSO (negative control), and they were then evaluated by flow cytometry. (A–F) Graphs show the number of cells/mg tumor for total CD8 (A), IFN-γ–producing CD8 (B), IFN-γ plus GzmB–producing CD8 (C), total CD4 (D), IFN-γ–producing CD4 (E), and IFN-γ plus GzmB–producing CD4 (F). (G) Unstimulated TILs were also evaluated for CD8 and HPV16 E7 tetramer. (H and I) An ELIspot assay was performed on splenocytes using overlapping 15-mer peptides for HPV16 E6 (H) and HPV18 E6 (I). Medians are shown. Mann-Whitney U test was used. *P < 0.05, **P < 0.01. TILs, tumor-infiltrating lymphocytes; TME, tumor microenvironment; VP, virus particles.

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