VG161 is an oncolytic HSV-1 with an ICP34.5 deletion and armed with multiple immunomodulatory factors. The absence of ICP34.5 restricts viral replication in neurons while conferring tumor specificity. However, this modification attenuates viral replication in tumor cells compared to wild-type HSV-1. Radiotherapy (RT) has been reported to promote viral replication and exert an immune-priming effect. Based on this, we hypothesize that RT could potentiate both the VG161 replication and its antitumor efficacy in breast cancer (BC). Our findings suggest that the optimal regimen for combining VG161 with RT involves administering 5 Gy irradiation 6 h after VG161 infection, which ensures that RT maximally promotes VG161 replication in BC. This enhancement in VG161 replication is mediated by the upregulation of GADD34 and HVEM induced by RT. Moreover, RT augments the expression of immunostimulatory transgenes carried by VG161 and immunogenic cell death of BC cells. In vivo, VG161 combined with RT demonstrates superior antitumor efficacy compared with either monotherapy in BC. Mechanistic investigations reveal that this combination therapy increases the abundances of tumor-infiltrating lymphocytes and elicits potent systemic antitumor immunity that inhibits local tumors and regresses abscopal metastases. The observed synergistic effect of VG161 and RT encourages further clinical translation.

Oncolytic virotherapy has evolved from a platform predicated on lysis of cancer cells into a sophisticated system for intratumoural immune reprogramming; the prevailing 'cold-to-hot' paradigm captures only part of this potential. A fundamental limitation shared by immune checkpoint inhibitors (ICIs) and early-generation oncolytic viruses (OVs) is a reliance on pre-existing tumour-specific T cells (TSTs), which presents an immunological ceiling that constrains antitumour activity - given that these agents have a limited capacity to generate TSTs de novo. Next-generation OVs overcome this constraint by functioning as agents for antigen-agnostic in situ cancer vaccination: intratumoural infection triggers immunogenic cell death, releasing potentially the full cancer proteome under pathogen-associated and/or damage-associated molecular pattern adjuvant conditions, thereby driving T cell priming against patient-specific neoantigens. In this Perspective, we delineate four pillars for the development of next-generation OVs. First, intratumoural vaccination as immunological ignition, with initial clinical data demonstrating T cell clonotype broadening, abscopal tumour regression and survival benefit in patients with ICI-refractory disease. Second, optimized payload-driven immune priming to hyperactivate antigen-presenting cells. Third, revised efficacy evaluation and end points using response criteria as well as novel biological correlates that better capture delayed and abscopal immune-mediated tumour control. Fourth, OV as the foundational immuno-oncology platform: according to the 'triple-A' framework encompassing admission, availability and activation of TSTs, next-generation, payload-engineered OVs uniquely satisfy all prerequisites for antitumour immunity simultaneously, with evidence from clinical trials of such agents supporting an 'OV-prime, ICI-amplify' strategy. Notably, OVs are systemic immune-reprogramming platforms that are delivered locally, not local therapies with incidental systemic effects.

Hepatocellular carcinoma remains a life-threatening malignancy with limited therapeutic options following the failure of second-line treatments1,2. Oncolytic viruses selectively replicate in and lyse cancer cells, releasing neoantigens and stimulating systemic antitumour immunity3, offering a potential therapeutic option. Here we present the results of a multicentre phase 1 clinical trial evaluating VG161, an engineered oncolytic herpes simplex virus that expresses IL-12, IL-15, IL-15Rα and a PD-1-PD-L1-blocking fusion protein4, for safety and efficacy in patients with advanced liver cancer. VG161 was well tolerated, with no dose-limiting toxicities observed, and it demonstrated promising efficacy by reshaping the tumour immune microenvironment and re-sensitizing tumours that were previously resistant to systemic treatments. Notably, we also found that patients who had previously been sensitive to checkpoint inhibitor therapy showed enhanced efficacy with VG161 treatment. Furthermore, we developed an efficacy-prediction model based on differentially expressed genes, which successfully identified patients who were likely to benefit from VG161 and predicted prolonged overall survival. These findings position VG161 as a promising third-line therapeutic option for refractory hepatocellular carcinoma. This provides a new avenue for treatment and advances the field of oncolytic virus-based immunotherapies. ClinicalTrials.gov registration: NCT04806464 .

BACKGROUND:Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy with limited treatment options and poor prognosis, especially for patients who failed standard therapies. OBJECTIVE:To explore the safety, efficacy and immunological mechanisms of the novel edition of oncolytic virus vaccination, VG161, a multiarmed oncolytic herpes simplex virus-1 expressing interleukin (IL)-12, IL-15 and a programmed death-ligand 1 antagonist, in patients with advanced ICC. DESIGN:This pooled analysis integrates data from two multicentre clinical studies: a Phase I dose-escalation study and a Phase IIa exploratory study. 24 patients with advanced ICC received ultrasound-guided intratumoral injections of VG161. Multiomics analyses were performed on longitudinal tumour biopsies to evaluate immune modulation. RESULTS:The oncolytic virus therapy VG161 was well tolerated and showed encouraging antitumour activity, including improved overall survival versus second-line FOLFOX chemotherapy, even though most patients received VG161 as third-line or later therapy. Notably, patients previously treated with immune checkpoint inhibitors (CPIs) experienced enhanced benefit. Multiomics profiling of longitudinal biopsies revealed significant remodelling of the immunosuppressive tumour microenvironment, with proliferated infiltration of antigen-presenting cells, CD8+ T cell activation and M2-like macrophage depletion. Single-cell and spatial transcriptomics identified epithelial and macrophage subpopulations (Epi-C2 and Macro-C1QC) as potential biomarkers of response and resistance. CONCLUSION:These early-phase findings suggest that VG161 elicits meaningful immune activation in ICC and supports further investigation. By inducing both direct oncolysis and multilayered immune activation, VG161 shows clinical benefit in a heavily pretreated population and holds promise for integration with CPI-based regimens. Validation in larger trials is warranted.

Therapeutic mRNA vaccines are limited in inducing tumor shrinkage in advanced cancers due to their inability to overcome immune-suppressive mechanisms within tumors. In this study, we developed an HPV-immunogen-expressing oncolytic virus (OV) using HSV-1 for HPV-related cancer treatment. A mouse syngeneic tumor model evaluates the effectiveness of intratumoral OV application for E6+E7+ tumors. Comparative analysis of OV and mRNA vaccines reveals distinct mechanisms in tumor treatment. Single-cell RNA sequencing and flow cytometry show that OV enhances cytotoxic T cell infiltration, polarizes neutrophils and macrophages toward anti-tumor phenotypes, and promotes immune activation within the tumor. In contrast, the mRNA vaccine more effectively activates peripheral antigen-specific T cell responses. A heterologous prime-boost strategy using the mRNA vaccine to prime systemic T cells, followed by OV therapy to direct these cells into the tumor, leads to significant tumor regression. This combination optimizes both systemic and intratumoral immune responses for advanced HPV-related cancers.

e14605 Background: Advanced hepatocellular carcinoma has a rapid progression and poor prognosis. Although drugs have been approved as standard therapies, they are prone to recurrence and metastasis after treatment and have poor long-term efficacy, and improvement of their survival status has been an important therapeutic goal for advanced hepatocellular carcinoma. In addition to direct tumour lysis, VG161 carries IL-12, IL-15/15Rα, and PDL1B that can synergistically exert anti-tumour immune stimulatory effects. In this study we intended to evaluate the safety and efficacy of VG161 in combination with the PD-1 inhibitor Camrelizumab for the treatment of advanced hepatocellular carcinoma. Methods: This study was a multicentre, open-label, single-arm design Phase Ib/IIa clinical study in two phases. As of 31 December 2024, a total of 16 patients were enrolled. The first phase is a dose-escalation phase that explores safety in two dose levels using a standard 3+3 design. The second phase is a dose-expansion phase that evaluates the safety and efficacy of VG161 in combination with Camrelizumab in the treatment of hepatocellular carcinoma. Administration was 1.0*10^8 PFU of VG161 per dose, once daily, administered by intratumoural injection for 2 or 3 consecutive days on days 1-3 of each cycle; the dose of Camrelizumab was 3 mg/kg, intravenously, once per cycle. Camrelizumab was administered 21 days per cycle, 7 days after the first dose of VG161. Results: The 16 participants were all Asian, of Han Chinese ethnicity, 15 males and 1 female, with a mean age of 55.4 years. There were 1 patients in the second line and 15 patients in the third line and above. All participants had been treated with immune checkpoint inhibitor medication. All 16 participants did not achieve MTD, a total of 16 participants (100%) had at least 1 TEAE, 11 patients (68.8%) had a grade ≥3 TEAE, and the most common grade ≥3 TEAE was a decreased lymphocyte count (43.8%). The most common TEAEs associated with study drug were fever (81.3%), reactive capillary hyperplasia (62.5%), hypoalbuminaemia (62.5%), and anaemia (62.5%). 11 of 16 participants could be assessed for response. After a median follow-up of 7.8 (range 3.2 to 11.9), 2 participants achieved PR and 8 participants achieved SD with an ORR of 18.2%. The median PFS was 6.3 (95% CI 4.1, NA) and the 6-month OS rate was 87.5%. Conclusions: The combination of VG161 and Camrelizumab demonstrated excellent anti-tumour activity with an acceptable safety profile in patients with hepatocellular carcinoma who failed even first-line standard therapy. Administration of VG161 3*10^8 PFU plus Camrelizumab 3 mg/kg per cycle is identified as RP2D. Further clinical studies are ongoing. Clinical trial information: NCT06124001 .

Tumor vaccines have shown clinical promise in treating certain cancers. However, their long-term effectiveness is often hindered by two major challenges: 1. The immune-suppressive tumor microenvironment (TME). 2. Selective targeting of antigen-positive tumor cells, which can lead to the expansion of antigen-negative cells and eventual tumor relapse. To address these challenges, we explored a combination approach using mRNA tumor vaccines and oncolytic virotherapy in HPV and HER2 mouse tumor models. Our findings reveal that while mRNA vaccines effectively eradicate antigen-positive tumors and suppress tumor growth, resistance quickly emerges, enabling tumors to evade the vaccine's effects. When mRNA vaccination was followed by intratumoral administration of an oncolytic virus—either with or without HPV or HER2 antigen expression—a significantly more durable anti-tumor response was achieved in both models. The oncolytic virus initiated broad tumor antigen presentation by lysing tumor cells, releasing diverse tumor-associated antigens, and increasing the overall antigenic load within the tumor. Furthermore, the lytic activity of the virus reprogrammed the TME, transforming it from an immune-suppressive environment into one more favorable for anti-tumor immune responses. This combination therapy elicited a potent local immune response, leveraging enhanced antigen presentation by the virus. The modified TME allowed the systemic immune response generated by the mRNA vaccine to penetrate and act effectively within the tumor. Additionally, the treatment induced systemic antigen-specific T-cell responses, and treated animals developed resistance to subsequent tumor challenges, demonstrating the establishment of immune memory. Our study highlights the unique role of oncolytic virotherapy as an intratumoral "boost" mechanism. By lysing tumor cells, oncolytic viruses amplify the range of tumor antigens presented to the immune system and reshape the TME to support robust immune activity. This synergy between mRNA vaccination and oncolytic virotherapy—when employed in a prime-boost regimen—produces a powerful and durable anti-tumor immune response that is both localized and systemically protective against recurrence. In conclusion, this research underscores the potential of combining mRNA tumor vaccines with oncolytic virotherapy to overcome immune evasion mechanisms, enhance tumor antigen presentation, and reprogram the TME, providing a promising strategy for achieving long-lasting anti-tumor immunity. William WEI GUO Jia. Oncolytic viruses as in situ personalized tumor vaccines for durable efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 953.

BACKGROUND:YOXINTINE contains >98 % of 20(S)-protopanaxadial (PPD), a metabolic product of ginsenosides with pre-clinical neuroprotective activity. Animal experiments and previous studies have shown that PPD has good antidepressant effect and safety. PURPOSE:To evaluate YOXINTINE in treating depression compared with a placebo in Chinese patients. STUDY DESIGN:This was a multicenter, double-blinded, randomized, placebo-controlled, phase 2 clinical trial. METHODS:The study included 178 randomized (1:1:1) Chinese patients with depression. Patients were randomly assigned to receive oral YOXINTINE at doses of 200 or 400 mg or a placebo administered twice daily for 8 weeks. The primary outcome was assessed by measuring changes in the Montgomery-Asberg Depression Rating Scale (MADRS) total score. All adverse reactions were recorded. All demographic and baseline characteristics were comparable. RESULTS:The changes in MADRS total scores from baseline were -10.43 for the placebo group, -16.24 for the 200 mg YOXINTINE group, and -13.60 for the 400 mg YOXINTINE group. The differences in MADRS total score changes compared with the placebo were -5.81 (95 % CI: -7.69, -3.92; P < 0.0001) and -3.17 (95 % CI: -5.08, -1.25; P = 0.0013) for the 200 mg and 400 mg groups, respectively. The results indicated a significantly greater MADRS score reduction in the 200 mg group (P = 0.0058, 95 % CI: 0.78, 4.51). Adverse event incidence was comparable among all groups. CONCLUSION:Oral YOXINTINE is safe and significantly improves depressive symptoms. PPD may exhibit antidepressant properties through mechanisms distinct from monoamine reuptake inhibition. REGISTRATION NUMBER:ChiCTR2300070568.

4105 Background: This study aims to investigate the safety and anti-tumor activity of VG161 expressing IL12, IL15/IL15 receptor α unit, and PD-L1 blocking peptide in patients with HCC refractory to standard therapies. Methods: The study was conducted as a multicenter phase I trial with fast titration and 3+3 dose escalation part (A) and expansion part (B), which enrolled patients with primary liver cancer refractory to standard therapies. Patients in part A were dosed in 5 cohorts on days 1, 2 and 3 by image-guided intratumoral injections with dosing ranges from 1.0×10^8 to 5×10^8 PFU per 28 days treatment cycles. Part B used a single arm Simon's two-stage design at the recommended phase 2 dose (RP2D). The study endpoints were safety, and efficacy assessed by objective response rate (ORR) and Disease Control Rate (DCR) by RECIST1.1 and mRECIST (HCC), PFS and OS. Pretreatment HCC tumor samples were collected and analyzed by RNAseq. Results: 44 patients including 40 HCC (Male/Female: 37/3; median age: 58years) were dosed and no DLTs were reported. The most common Treatment-Related Adverse Events (TRAEs) was fever, which was resolved with symptomatic treatment. RP2D was determined as 1ⅹ10^8 PFU daily on day 1, 2 and 3 of each cycle. Of 40 HCC patients, 35 failed after 2 prior lines of therapy and were eligible for tumor assessment. ORR was 17.14% (6/35), DCR was 60.00% (21/35). The median PFS and OS were 2.90 (95%CI: 1.85-3.95) and 9.40 (95%CI: 0.47-18.33) months respectively. Statistically significant OS prolongation was observed in a subgroup of 22 HCC patients who progressed after receiving at least 3 months of CPI (PreCPI>3 m) as compared to those who received CPI for ≤3 months (PreCPI ≤ 3 m). The median OS was 17.30 months (95%CI: 5.35-29.25) vs. 7.40 months (95%CI: 5.11-9.69), HR: 0.32 (95%CI: 0.10 to 0.98) (p<0.05). Patients who received targeted or CPI therapies after VG161 survived longer than those who did not receive any anticancer treatment although they all previously failed such therapies [20.10 months (95%CI: 13.19-27.01) vs. 8.80 months (95%CI: 6.34-11.26), HR: 0.30 (95%CI: 0.10-0.88), P<0.05]. PreCPI>3 m and anti-cancer treatment after VG161 were the 2 independent factors with significant impact on OS (P<0.05). A gene signature was identified based on RNAseq data which predicted the prolonged OS in the study patients (P<0.01) but not in patients retrieved from TCGA database. Conclusions: VG161 was well tolerated and demonstrated comparable ORR and DCR with other CPIs data in 2L HCC. VG161 also prolonged survival in a subgroup of patients identified by prior treatment or gene signature, supporting further studies with enrichment of patients who may benefit from the treatment. The implications of pre/post VG161 CPI treatment on OS underscore a combination strategy for improving outcomes. Clinical trial information: NCT04806464 .

Abstract Tumor vaccines, particularly the innovative mRNA variants, hold immense promise in cancer immunotherapy. Despite their potential, these vaccines encounter formidable challenges in surmounting immune tolerance, the immune-suppressive tumor microenvironment (TME) and more importantly, the resistance developed in cancer cells that are antigen negative. Concurrently, oncolytic virotherapy (OV), a distinct facet of tumor vaccination, significantly alters the TME and releases tumor antigens via lysis to generate a broader spectrum of tumor antigens. This unique property positions OV to induce anti-tumor immunity, as evidenced by prolonged overall survival and abscopal tumor suppression. Recognizing the complementary strengths of mRNA tumor vaccines and OV, we propose a combined approach to address the limitations inherent in each modality. Our study tested this hypothesis by combining a mRNA vaccine targeting HER2 with oncolytic viruses, utilizing a prime-boost strategy on a HER2-expressing CT26 mouse tumor model. Notably, while the mRNA vaccine alone induced specific anti-HER2 systemic immunity, the combination demonstrated a potent immune response against both anti-HER2 and anti-CT26, leading to durable tumor eradication. Our findings highlight that peripheral vaccination has the potential to elicit an immune response in non-immune suppressive environments. However, combining it with virotherapy not only amplifies specific immunity but also induces a broader immune response against a spectrum of tumor antigens. This synergistic combination represents a promising avenue for advancing cancer immunotherapy, offering the potential for improved treatment outcomes and broader applicability of tumor vaccines across diverse cancer types. Citation Format: William Jia. Tumor vaccines and oncolytic virotherapy: systemic immunity vs. tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C005.

Abstract The emergence of nucleic acid medicine (NAM) has profoundly addressed global infectious disease challenges1 and revolutionized cancer therapy2 and gene-editing3. However, current NAM, such as mRNA vaccine, remains distant from customizable supply and is fraught with hurdles of thermo-instability and infrastructure dependence. Drawing inspiration from the efficiency of capsule coffee machines, we introduce a Rapid On-site Microfluidic Assembly (ROMA) prototype capable of generating ready-to-inject mRNA vaccines at a throughput of 180 doses/hour (∼100 µg mRNA/dose). Analogous to the varied flavors of capsule coffee, our ROMA prototype offers personalized options for mRNA vaccines, including lipid nanoparticle (LNP) sizes, compositions, mRNA types, and dosages tailored to individual needs. Diverging from traditional mechanism of directly assembling mRNA and lipids into mRNA-LNPs, ROMA technology utilizes mRNA and pre-made empty LNPs to form mRNA-LNPs. Nevertheless, ROMA mRNA vaccine exhibits equivalent physiochemical parameters and in-vivo expressions compared to conventional ones, with a benefit of lower toxicity. Crucially, ROMA mRNA vaccine, immediately deployable without the need for storage, fundamentally avoids the thermal instability and degradation risks associated with conventional mRNA vaccines. This transformative ROMA technology offers unparalleled user-end convenience, unlocking the potential for personalized mRNA vaccines and treatments, thereby significantly expanding the scope of NAM therapeutics.

The efficacy and safety of self-amplifying mRNA (saRNA) have been demonstrated in COVID-19 vaccine applications. Unlike conventional non-replicating mRNA (nrmRNA), saRNA offers a key advantage: its self-replication mechanism fosters efficient expression of the encoded protein, leading to substantial dose savings during administration. Consequently, there is a growing interest in further optimizing the expression efficiency of saRNA. In this study, in vitro adaptive passaging of saRNA is conducted under exogenous interferon pressure, which revealed several mutations in the nonstructural protein (NSP). Notably, two stable mutations, Q48P and I113F, situated in the NSP3 macrodomain (MD), attenuated its mono adenosine diphosphate ribose (MAR) hydrolysis activity and exhibited decreased replication but increased payload expression compared to wild-type saRNA (wt saRNA). Transcriptome sequencing analysis unveils diminished activation of the double-stranded RNA (dsRNA) sensor and, consequently, a significantly reduced innate immune response compared to wt saRNA. Furthermore, the mutant saRNA demonstrated less translation inhibition and cell apoptosis than wt saRNA, culminating in higher protein expression both in vitro and in vivo. These findings underscore the potential of reducing saRNA replication-dependent dsRNA-induced innate immune responses through genetic modification as a valuable strategy for optimizing saRNA, enhancing payload translation efficiency, and mitigating saRNA cytotoxicity.

Abstract Persistent human papillomavirus (HPV) infection is linked to several malignancies, highlighting the need for effective therapeutic vaccines. In this study, we tested a lipid nanoparticle-encapsulated mRNA vaccine expressing tHA-mE7-mE6. By mutating the E6 and E7 proteins to reduce their tumorigenicity and fusing them with a truncated influenza hemagglutinin protein (tHA) for better antigen uptake, we improved the vaccine’s efficacy. The tHA-mE7-mE6 mRNA vaccine showed superior results compared to mE7-mE6 mRNA, achieving complete tumor regression and preventing new tumors in an E6 and E7 positive model. It elicited a strong CD8+ T-cell response, with antigen-specific CD8+ T-cells found in the spleen, blood, and tumors. Additionally, the therapy increased DC and NK cell infiltration into tumors. Overall, this study demonstrates that the tHA-mE7-mE6 mRNA vaccine induces a potent anti-tumor immune response, showing promise for treating HPV-induced cancers and preventing recurrence. Citation Format: William Jia. Preventing and treating HPV-related Cancer with mRNA Therapy Expressing A DC-targeting Antigen [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr PR003.

Sarcoma is derived from mesenchymal neoplasms and has numerous subtypes, accounting for 1% of all adult malignancies and 15% of childhood malignancies. The prognosis of metastatic or recurrent sarcoma remains poor. The current study presents two cases of sarcoma enrolled in a phase I dose escalation trial for solid tumor, who had previously failed all standard therapies. These patients were treated with VG161, an immune-stimulating herpes simplex virus type 1 oncolytic virus with payloads of IL-12, IL-15 and IL-15 receptor alpha unit, and a programmed cell death 1 (PD-1)/PD-1 ligand 1 blocking peptide. Both cases demonstrated stable disease as the best response, accompanied by a noteworthy prolongation of progression-free survival (11.8 months for chondrosarcoma and 11.9 months for soft tissue sarcoma, respectively) at a dose of 2.5x108 PFU/cycle. In addition, the treatment led to the activation of anti-cancer immunity, as evident from cytokine, lymphocyte subset and related pathway analyses of peripheral blood and/or tumor biopsy samples. These promising results suggest that VG161 monotherapy holds promise as an effective treatment for sarcoma and warrants further investigation through clinical trials. The two reported patients were part of a phase I clinical trial conducted and registered on the Australian New Zealand Clinical Trials Registry in Australia (registration no. ACTRN12620000244909; registration date, 26 February, 2020).

Persistent human papillomavirus (HPV) infection is associated with multiple malignancies. Developing therapeutic vaccines to eliminate HPV-infected and malignant cells holds significant value. In this study, we introduced a lipid nanoparticle encapsulated mRNA vaccine expressing tHA-mE7-mE6. Mutations were introduced into E6 and E7 of HPV to eliminate their tumourigenicity. A truncated influenza haemagglutinin protein (tHA), which binds to the CD209 receptor on the surface of dendritic cells (DCs), was fused with mE7-mE6 in order to allow efficient uptake of antigen by antigen presenting cells. The tHA-mE7-mE6 (mRNA) showed higher therapeutic efficacy than mE7-mE6 (mRNA) in an E6 and E7+ tumour model. The treatment resulted in complete tumour regression and prevented tumour formation. Strong CD8+ T-cell immune response was induced, contributing to preventing and curing of E6 and E7+ tumour. Antigen-specific CD8+ T were found in spleens, peripheral blood and in tumours. In addition, the tumour infiltration of DC and NK cells were increased post therapy. In conclusion, this study described a therapeutic mRNA vaccine inducing strong anti-tumour immunity in peripheral and in tumour microenvironment, holding promising potential to treat HPV-induced cancer and to prevent cancer recurrence.