Salomon et al. showed in two mouse models that a single subtherapeutic i.v. dose of HPV-E7 RNA lipoplex vaccine synergized with high-dose local radiotherapy (LRT) to promote rejection of HPV16 E6/E7+ tumors. This depended on total LRT dose, not dose fractionation. Vaccine with or without LRT increased intratumoral CD8+ cells, CD4+ cells, NK cells, and PD-L1+CD11b+ myeloid cells, and MHC-I and PD-L1 on tumor cells. E7-specific CD8+ T cells were enriched in tumors, spleens, and LNs, and upon ex vivo antigen restimulation, made IFNγ/TNFα. LRT increased tumor cell apoptosis and reduced tumor mass and hypoxia to sensitize tumor cells to antigen-specific T cell killing.
Contributed by Paula Hochman
ABSTRACT: Human papilloma virus (HPV) infection is a causative agent for several cancers types (genital, anal and head and neck region). The HPV E6 and E7 proteins are oncogenic drivers and thus are ideal candidates for therapeutic vaccination. We recently reported that a novel ribonucleic acid lipoplex (RNA-LPX)-based HPV16 vaccine, E7 RNA-LPX, mediates regression of mouse HPV16(+) tumors and establishes protective T cell memory. An HPV16 E6/E7 RNA-LPX vaccine is currently being investigated in two phase I and II clinical trials in various HPV-driven cancer types; however, it remains a high unmet medical need for treatments for patients with radiosensitive HPV16(+) tumors. Therefore, we set out to investigate the therapeutic efficacy of E7 RNA-LPX vaccine combined with standard-of-care local radiotherapy (LRT). We demonstrate that E7 RNA-LPX synergizes with LRT in HPV16(+) mouse tumors, with potent therapeutic effects exceeding those of either monotherapy. Mode of action studies revealed that the E7 RNA-LPX vaccine induced high numbers of intratumoral-E7-specific CD8(+) T cells, rendering cold tumors immunologically hot, whereas LRT primarily acted as a cytotoxic therapy, reducing tumor mass and intratumor hypoxia by predisposing tumor cells to antigen-specific T cell-mediated killing. Overall, LRT enhanced the effector function of E7 RNA-LPX-primed T cell responses. The therapeutic synergy was dependent on total radiation dose, rather than radiation dose-fractionation. Together, these results show that LRT synergizes with E7 RNA-LPX and enhances its anti-tumor activity against HPV16(+) cancer models. This work paves into a new translational therapy for HPV16(+) cancer patients.
Author Info: (1) TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Freiligrathstra§e 12, 55131, Mainz, Germany. (2) TRON - Translational
Author Info: (1) TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Freiligrathstra§e 12, 55131, Mainz, Germany. (2) TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Freiligrathstra§e 12, 55131, Mainz, Germany. (3) Biopharmaceutical New Technologies (BioNTech) SE, Mainz, Germany. (4) TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Freiligrathstra§e 12, 55131, Mainz, Germany. Comprehensive Cancer Centre, King's College London, London, UK. (5) TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Freiligrathstra§e 12, 55131, Mainz, Germany. (6) TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Freiligrathstra§e 12, 55131, Mainz, Germany. (7) TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Freiligrathstra§e 12, 55131, Mainz, Germany. Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany. (8) TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Freiligrathstra§e 12, 55131, Mainz, Germany. Biopharmaceutical New Technologies (BioNTech) SE, Mainz, Germany. (9) TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Freiligrathstra§e 12, 55131, Mainz, Germany. Biopharmaceutical New Technologies (BioNTech) SE, Mainz, Germany. (10) Biopharmaceutical New Technologies (BioNTech) SE, Mainz, Germany. (11) Biopharmaceutical New Technologies (BioNTech) SE, Mainz, Germany. Research Center for Immunotherapy (FZI), University Medical Center at the Johannes Gutenberg University, Mainz, Germany. (12) TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Freiligrathstra§e 12, 55131, Mainz, Germany. fulvia.vascotto@tron-mainz.de.
