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.
Highlights
Human papilloma virus (HPV) is the most frequently sexually transmitted viral infection [1] and, owing to the expression of the viral oncogenes E6 and E7, is an essential driver in the induction of genital, anogenital and head and neck cancers [2]
In order to evaluate the combination of E7 ribonucleic acid lipoplex (RNA-LPX) and local radiotherapy (LRT), we designed a schedule employing a subtherapeutic dose of E7 RNA-LPX followed by different doses of LRT in mice bearing well-established HPV16 E6/E7+ TC-1 tumors
Greatest anti-tumor efficacy was achieved when E7 RNALPX was combined with double treatment of high-dose LRT (12 Gy), rendering 100% of mice tumor-free up to 100 days after tumor inoculation (Fig. 1b) – a schedule that was chosen for subsequent experiments, dispensing the second irradiation to allow the collection of samples for characterization of the tumor immunemicroenvironment by flow cytometry
Summary
HPV is the most frequently sexually transmitted viral infection [1] and, owing to the expression of the viral oncogenes E6 and E7, is an essential driver in the induction of genital, anogenital and head and neck cancers [2]. HPV+ HNSCCs generally have a more favorable prognosis [5] and, due to the deregulation of the cell cycle and deoxyribonucleic acid (DNA) repair by the oncoproteins E6 and E7, are more radiosensitive than their radioresistant HPV− counterpart [6] as they accumulate unrepaired doublestrand breaks and undergo cell cycle arrest G2 [7]. In addition to their contribution to radiosensitivity, the oncoproteins E6 and E7 are exclusively expressed in tumor tissue and are highly foreign to the immune system, rendering them ideal candidates for therapeutic anti-cancer vaccination. Similar observations were made by others using HPV16 DNA [18, 19] or peptidebased [20,21,22] vaccines
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