Treatment of HPV-Related Uterine Cervical Cancer with a Third-Generation Oncolytic Herpes Simplex Virus in Combination with an Immune Checkpoint Inhibitor

Sep 24, 2026

Cervical cancer remains a leading malignancy in women, and current immune checkpoint inhibitor (ICI) strategies show insufficient efficacy. Oncolytic virus therapy may raise tumor immunogenicity and strengthen ICI antitumor activity. In a bilateral syngeneic murine model for HPV-related cervical cancer, the study evaluates a triple-mutated oncolytic herpes virus (T-01) combined with an ICI, assessing tumor control, T-cell responses, and viral isolation outcomes.

LanguageEnglish

CategoryResearch & Report

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Pages11

Reading Time28 min

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Abstract

Introduction

Background: incidence, mortality, and current treatments

HPV-driven immunosuppression and rationale for immunotherapy

ICI clinical evidence and limitations

Article Treatment of HPV-Related Uterine Cervical Cancer with a Third-Generation Oncolytic Herpes Simplex Virus in Combination with an Immune Checkpoint Inhibitor Masahiro Kagabu 1, *, Naoto Yoshino 2, Kazuyuki Murakami 1, Hideki Kawamura 1, Yutaka Sasaki 2, Yasushi Muraki 2 and Tsukasa Baba 1 Citation: Kagabu, M.; Yoshino, N.; Murakami, K.; Kawamura, H.; Sasaki, Y.; Muraki, Y.; Baba, T. Treatment of HPV-Related Uterine Cervical Cancer with a Third-Generation Oncolytic Herpes Simplex Virus in Combination with an Immune Checkpoint Inhibitor. Int. J. Mol. Sci. 2023, 24, 1988. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/ijms24031988](10.3390/ijms24031988) Academic Editor: Laura Menotti Received: 4 December 2022 Revised: 11 January 2023 Accepted: 16 January 2023 Published: 19 January 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Department of Obstetrics and Gynecology, School of Medicine, Iwate Medical University, Shiwa 028-3695, Iwate, Japan 2 Division of Infectious Diseases and Immunology, Department of Microbiology, School of Medicine, Iwate Medical University, Shiwa 028-3694, Iwate, Japan * [Correspondence: mkagabu@iwate-med.ac.jp](Correspondence: mkagabu@iwate-med.ac.jp); Tel.: +81-19-613-7111 Abstract: Cervical cancer is one of the most common cancers in women. The development of new therapies with immune checkpoint inhibitors (ICIs) is being investigated for cervical cancer; however, their efﬁcacy is not currently sufﬁcient. Oncolytic virus therapy can increase tumor immunogenicity and enhance the antitumor effect of ICIs. In this report, the therapeutic potential of a triple-mutated oncolytic herpes virus (T-01) with an ICI for human papillomavirus (HPV)-related cervical cancer was evaluated using a bilateral syngeneic murine model. The efﬁcacy of intratumoral (i.t.) administration with T-01 and subcutaneous (s.c.) administration of anti-programmed cell death ligand 1 (PD-L1) antibody (Ab) was equivalent to that of anti-PD-L1 Ab alone on the T-01-injected side. Moreover, combination therapy had no signiﬁcant antitumor effect compared to monotherapy on the T-01-noninjected side. Combination therapy signiﬁcantly increased the number of tumor speciﬁc T cells in the tumor. While T-01 could not be isolated from tumors receiving combination therapy, it could be isolated following T-01 monotherapy. Furthermore, T-01 had a cytotoxic effect on stimulated T cells. These results suggest that T-01 and anti-PD-L1 Ab partially counteract and therefore concomitant administration should be considered with caution. Keywords: cervical cancer; oncolytic virus; herpes simplex virus; oncolytic viral therapy; immune checkpoint inhibitor 1. Introduction Cervical cancer is the fourth most common cancer in women, and the seventh most common of all human cancers. The global incidence of and mortality from cervical cancer in 2020 were approximately 604,000 and 341,000, respectively, according to the Agency for Research on Cancer (IARC) database [1] . Tumor metastasis is the most common cause of death in cervical cancer. Currently, radiotherapy and chemotherapy have been used to treat patients with advanced uterine cervical cancer [2], but with limited success. Moreover, the available chemotherapeutic agents have only limited efﬁcacy against recurrent disease. Therefore, new therapeutic strategies for advanced and recurrent cervical cancers are urgently needed. Cervical cancer is caused by persistent human papillomavirus (HPV) infection. HPVE6 and E7 induce a cascade of interleukin 6 (IL6) cytokine and T-cell signaling [3] . Increased IL6 subsequently induces myelo/monocyte inﬁltrat

FAQs

Why are immune checkpoint inhibitors not fully effective for cervical cancer?

ICI efficacy is limited, partly due to features of “cold tumors” such as absent or low tumor T-cell infiltration, leading to early resistance. The review of clinical trends notes benefit but not sufficient overall control.

What is the rationale for using an oncolytic herpes virus with ICIs?

Oncolytic virus therapy can increase tumor immunogenicity and enhance the antitumor effect of ICIs. The study evaluates a triple-mutated oncolytic herpes virus (T-01) as part of this strategy.

How did combination therapy affect tumor outcomes compared with monotherapy?

On the T-01-injected side, the intratumoral T-01 plus anti-PD-L1 antibody effects were equivalent to anti-PD-L1 antibody alone. On the noninjected side, combination therapy showed no significant antitumor effect versus monotherapy.

Sep 24, 2026

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