Peng et al. observed that intratumoral, as opposed to intramuscular, administration of an HPV16 E6/E7 oncoprotein fusion vaccine elevated E7-specific CD8+ T cells and reduced Tregs in tumors and peripheral blood and controlled both injected and distal tumors, extending survival of TC-1 tumor-bearing mice. Vaccination with the fusion protein was more effective than long or short peptide vaccines and depended on the Batf3 pathway. Intratumoral vaccination upregulated PD-L1 on tumor cells and PD-1 on tumor-infiltrating CD8+ T cells, and synergized with anti-PD-1 therapy for improved therapeutic outcomes.
Contributed by Alex Najibi
INTRODUCTION: The human papillomavirus (HPV) encoded oncoproteins E6 and E7 are constitutively expressed in HPV-associated cancers, making them logical therapeutic targets. Intramuscular immunization of patients with HPV16 L2E7E6 fusion protein vaccine (TA-CIN) is well tolerated and induces HPV-specific cellular immune responses. Efficacy of PD-1 immune checkpoint blockade correlates with the level of tumor-infiltrating CD8_+_T cells, yet most patients lack significant tumor infiltration of immune cells making immune checkpoint blockade suboptimal. We hypothesized that intratumoral vaccination with TA-CIN could increase the number of tumor-infiltrating CD8_+_T cells, synergize with PD-1 blockade and result in better control of tumors compared with either PD-1 blockade or vaccination alone. METHODS: We examined the immunogenicity and antitumor effects of intratumoral vaccination with TA-CIN alone or in combination with PD-1 blockade in the TC-1 syngeneic murine tumor model expressing HPV16 E6/E7. RESULTS: Intratumoral vaccination with TA-CIN induced stronger antigen-specific CD8_+_T cell responses and antitumor effects. Intratumoral TA-CIN vaccination generated a systemic immune response that was able to control distal TC-1 tumors. Furthermore, intratumoral TA-CIN vaccination induced tumor infiltration of antigen-specific CD8_+_T cells. Knockout of Batf3 abolished antigen-specific CD8_+_T cell responses and antitumor effects of intratumoral TA-CIN vaccination. Finally, PD-1 blockade synergizes with intratumoral TA-CIN vaccination resulting in significantly enhanced antigen-specific CD8_+_T cell responses and complete regression of tumors, whereas either alone failed to control established TC-1 tumor. CONCLUSIONS: Our results provide rationale for future clinical testing of intratumoral TA-CIN vaccination in combination with PD-1 blockade for the control of HPV16-associated tumors.
Author Info: (1) Department of Pathology, The Johns Hopkins University, Baltimore, MD, USA. (2) Department of Otolaryngology, The Johns Hopkins University, Baltimore, MD, USA. (3) Department of
Author Info: (1) Department of Pathology, The Johns Hopkins University, Baltimore, MD, USA. (2) Department of Otolaryngology, The Johns Hopkins University, Baltimore, MD, USA. (3) Department of Pathology, The Johns Hopkins University, Baltimore, MD, USA. (4) Department of Pathology, The Johns Hopkins University, Baltimore, MD, USA. (5) Department of Pathology, The Johns Hopkins University, Baltimore, MD, USA. (6) Department of Pathology, The Johns Hopkins University, Baltimore, MD, USA. (7) Oncology, The Johns Hopkins University, Baltimore, MD, USA. Obstetrics and Gynecology, The Johns Hopkins University, Baltimore, MD, USA. (8) Department of Pathology, The Johns Hopkins University, Baltimore, MD, USA. Oncology, The Johns Hopkins University, Baltimore, MD, USA. (9) Department of Pathology, The Johns Hopkins University, Baltimore, MD, USA. Oncology, The Johns Hopkins University, Baltimore, MD, USA. Obstetrics and Gynecology, The Johns Hopkins University, Baltimore, MD, USA. (10) Department of Pathology, The Johns Hopkins University, Baltimore, MD, USA. wutc@jhmi.edu. Oncology, The Johns Hopkins University, Baltimore, MD, USA. wutc@jhmi.edu. Obstetrics and Gynecology, The Johns Hopkins University, Baltimore, MD, USA. wutc@jhmi.edu. Molecular Microbiology and Immunology, The Johns Hopkins University, Baltimore, MD, USA. wutc@jhmi.edu. Johns Hopkins School of Medicine, 1550 Orleans St, CRB II - Room 309, Baltimore, MD, 21287, USA. wutc@jhmi.edu.
