Therapeutic vaccines for human papillomavirus-related cancer: progress and challenges

Human papillomavirus (HPV) is the most global widespread sexually transmitted disease. In public health, the epidemiological importance of HPV infection is related to its ability to induce malignancy in epithelial cells (1). In fact, high-risk HPV is associated with virtually all cases of cervical cancer, which is the fourth most prevalent in women worldwide, and one of the leading causes of death. Actually, a woman dies of cervical cancer every two minutes (2). In this concern, a global strategy to eliminate cervical cancer was recently launched by the World Health Organization (WHO) (3). Importantly, persistent HPV infection is also related to other forms of cancer, including the vagina, vulva, anus, penile, tongue, and oropharynx. Prophylactic vaccines are one of the most essential disease-prevention practices, and screening early HPV lesions with different approaches can prevent cancer development. However, the landscape of HPV-related cancer and the recurrence rates following usual treatments highlights emerging trends in cancer treatment (4).

In the field of therapeutic vaccines, the focus of HPV research relies on strategies that deliver HPV oncoproteins to target immune cells (5-7), eliciting an antitumor response capable of controlling tumor development and achieving partial or total tumor remission. Furthermore, treatment combinations are required to boost the antitumor potential of a vaccine candidate (8-11). In this proposal, Lee et al. [2022] design vaccines based on HPV-16 E7 short or long peptides and tested different treatment approaches in a tumor-mouse model (12). The authors emphasize the importance of combining therapeutic vaccines with adjuvant and immune checkpoint inhibitor to reach a better outcome. Interestingly, an improved antitumor effect was observed when long peptides (E7-PL35) were adjuvanted with flagellin, especially when associated with anti-PDL1. The efficacy of synthetic long peptides of HPV-16 combined or not with chemotherapy or immune checkpoint inhibitors was well documented in clinical and preclinical trials (13-18), highlighting the potential of vaccines based on HPV-16 E7 long peptides to treat HPV pre-malignant and malignant lesions. Importantly, combined therapies showed to be essential to achieve strong and protective immune responses, especially for invasive cancer (18).

In preclinical studies, other vaccine platforms showed strong antitumor activity against HPV-related tumors. Diniz et al. [2010] and Porchia et al. [2011] developed two vaccine strategies with therapeutic potential against HPV 16-related tumors, one using naked DNA (19) and the other using recombinant protein (20). These vaccines are based on the production of a hybrid protein formed by the fusion of Herpes simplex virus-1 (HSV-1) glycoprotein D (gD) and the HPV 16 E7 oncoprotein (gDE7), which activate CD8⁺ E7-specific T cells and elicit a significant antitumor response in mice models. When combined with other techniques such as electroporation (10), IDO inhibitors (9), melatonin (9), polyinosinic:polycytidylic acid [poly(I:C)] (20), spores (11), chemotherapies (7,8), and IL-10 inhibitors (21), the antitumor potential of gDE7-based vaccines was boosted.

In recent years, a great advance in cancer research was observed regarding therapeutic vaccines. There is no doubt that cancer vaccines are the new frontiers of immunotherapy. High demand and expectations reside on cancer vaccines, with promising immuno-therapeutics possibility to reach a better outcome in cancer patients. Further studies targeting immune system mechanisms are necessary for translational research of ongoing vaccine candidates and for future vaccine designs.

Acknowledgments

Funding: Ana Carolina Ramos Moreno was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), grant 2015/16505-0, and fellow 2016/00708-1; Roberta Liberato Pagni was supported by FAPESP, fellow 2017/25544-4; Guilherme Formoso Pelegrin was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), fellow 139027/2021-1.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-2158/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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