Elimination of Human Papillomavirus 16-Positive Tumors by a Mucosal RAd5 Therapeutic Vaccination in a Pre-Clinical Murine Study

Overview

Journal Vaccines (Basel)

Date 2024 Sep 28

PMID 39339987

Authors

Molly R Braun

Anne C Moore

Jonathan D Lindbloom

Katherine A Hodgson

Emery G Dora

Sean N Tucker

Affiliations

Soon will be listed here.

Abstract

Therapeutic vaccination can harness the body's cellular immune system to target and destroy cancerous cells. Several treatment options are available to eliminate pre-cancerous and cancerous lesions caused by human papillomaviruses (HPV), but may not result in a long-term cure. Therapeutic vaccination may offer an effective, durable, and minimally intrusive alternative. We developed mucosally delivered, recombinant, non-replicating human adenovirus type 5 (rAd5)-vectored vaccines that encode HPV16's oncogenic proteins E6 and E7 alongside a molecular dsRNA adjuvant. The induction of antigen-specific T cells and the therapeutic efficacy of rAd5 were evaluated in a mouse model of HPV tumorigenesis where E6E7-transformed cells, TC-1, were implanted subcutaneously in C57BL/6 mice. After tumor growth, mice were treated intranasally with rAd5 vaccines expressing the wildtype form of E6E7 (rAd5-16/E6E7) in combination with an anti-PD-1 antibody or isotype control. Animals treated with rAd5-16/E6E7 with and without anti-PD-1 had significant reductions in tumor volume and increased survival compared to controls. Further, animals treated with rAd5-16/E6E7 had increased CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs) and produced a cytotoxic tumor microenvironment. In a second study, the immunogenicity of a non-transformative form of E6E7 (rAd5-16/E6E7) and a vaccine encoding predicted T cell epitopes of E6E7 (rAd5-16/E6E7) were evaluated. These vaccines elicited significant reductions in TC-1 tumor volume and increased survival of animals. Antigen-specific CD8+ T effector memory cells were observed in the animals treated with E6E7-encoding rAd5, but not in the rAd5-empty group. The work described here demonstrates that this mucosal vaccination can be used therapeutically to elicit specific cellular immunity and further identifies a clinical candidate with great potential for the treatment and prevention of human cervical cancer.

References

Stern P, van der Burg S, Hampson I, Broker T, Fiander A, Lacey C . Therapy of human papillomavirus-related disease. Vaccine. 2012; 30 Suppl 5:F71-82. PMC: 4155500. DOI: 10.1016/j.vaccine.2012.05.091. View

Ibrahim Khalil A, Zhang L, Muwonge R, Sauvaget C, Basu P . Efficacy and safety of therapeutic HPV vaccines to treat CIN 2/CIN 3 lesions: a systematic review and meta-analysis of phase II/III clinical trials. BMJ Open. 2023; 13(10):e069616. PMC: 10603536. DOI: 10.1136/bmjopen-2022-069616. View

de Sanjose S, Serrano B, Tous S, Alejo M, Lloveras B, Quiros B . Burden of Human Papillomavirus (HPV)-Related Cancers Attributable to HPVs 6/11/16/18/31/33/45/52 and 58. JNCI Cancer Spectr. 2019; 2(4):pky045. PMC: 6649711. DOI: 10.1093/jncics/pky045. View

McConnell E, Basit A, Murdan S . Measurements of rat and mouse gastrointestinal pH, fluid and lymphoid tissue, and implications for in-vivo experiments. J Pharm Pharmacol. 2007; 60(1):63-70. DOI: 10.1211/jpp.60.1.0008. View

Flitter B, Braun M, Tucker S . Drop the Needle; A Temperature Stable Oral Tablet Vaccine Is Protective against Respiratory Viral Pathogens. Vaccines (Basel). 2022; 10(4). PMC: 9031097. DOI: 10.3390/vaccines10040593. View

Kim L, Martinez C, Hodgson K, Trager G, Brandl J, Sandefer E . Systemic and mucosal immune responses following oral adenoviral delivery of influenza vaccine to the human intestine by radio controlled capsule. Sci Rep. 2016; 6:37295. PMC: 5121599. DOI: 10.1038/srep37295. View

Raskov H, Orhan A, Christensen J, Gogenur I . Cytotoxic CD8 T cells in cancer and cancer immunotherapy. Br J Cancer. 2020; 124(2):359-367. PMC: 7853123. DOI: 10.1038/s41416-020-01048-4. View

Scott E, Gocher A, Workman C, Vignali D . Regulatory T Cells: Barriers of Immune Infiltration Into the Tumor Microenvironment. Front Immunol. 2021; 12:702726. PMC: 8222776. DOI: 10.3389/fimmu.2021.702726. View

Juarez V, Pasolli H, Hellwig A, Garbi N, Arregui A . Virus-Like Particles Harboring CCL19, IL-2 and HPV16 E7 Elicit Protective T Cell Responses in HLA-A2 Transgenic Mice. Open Virol J. 2013; 6:270-6. PMC: 3547371. DOI: 10.2174/1874357901206010270. View

10.

Boursnell M, Rutherford E, Hickling J, Rollinson E, Munro A, Rolley N . Construction and characterisation of a recombinant vaccinia virus expressing human papillomavirus proteins for immunotherapy of cervical cancer. Vaccine. 1996; 14(16):1485-94. PMC: 7130629. DOI: 10.1016/s0264-410x(96)00117-x. View

11.

Bruni L, Saura-Lazaro A, Montoliu A, Brotons M, Alemany L, Diallo M . HPV vaccination introduction worldwide and WHO and UNICEF estimates of national HPV immunization coverage 2010-2019. Prev Med. 2021; 144:106399. DOI: 10.1016/j.ypmed.2020.106399. View

12.

McCarthy C, Youde S, Man S . Definition of an HPV18/45 cross-reactive human T-cell epitope after DNA immunisation of HLA-A2/KB transgenic mice. Int J Cancer. 2005; 118(10):2514-21. DOI: 10.1002/ijc.21643. View

13.

Simpson-Herren L, Lloyd H . Kinetic parameters and growth curves for experimental tumor systems. Cancer Chemother Rep. 1970; 54(3):143-74. View

14.

Jordanova E, Gorter A, Ayachi O, Prins F, Durrant L, Kenter G . Human leukocyte antigen class I, MHC class I chain-related molecule A, and CD8+/regulatory T-cell ratio: which variable determines survival of cervical cancer patients?. Clin Cancer Res. 2008; 14(7):2028-35. DOI: 10.1158/1078-0432.CCR-07-4554. View

15.

Trimble C, Clark R, Thoburn C, Hanson N, Tassello J, Frosina D . Human papillomavirus 16-associated cervical intraepithelial neoplasia in humans excludes CD8 T cells from dysplastic epithelium. J Immunol. 2010; 185(11):7107-14. PMC: 3075978. DOI: 10.4049/jimmunol.1002756. View

16.

Nielsen M, Lundegaard C, Worning P, Lauemoller S, Lamberth K, Buus S . Reliable prediction of T-cell epitopes using neural networks with novel sequence representations. Protein Sci. 2003; 12(5):1007-17. PMC: 2323871. DOI: 10.1110/ps.0239403. View

17.

Lee S, Yang A, Wu T, Hung C . Immunotherapy for human papillomavirus-associated disease and cervical cancer: review of clinical and translational research. J Gynecol Oncol. 2016; 27(5):e51. PMC: 4944018. DOI: 10.3802/jgo.2016.27.e51. View

18.

Lundegaard C, Lamberth K, Harndahl M, Buus S, Lund O, Nielsen M . NetMHC-3.0: accurate web accessible predictions of human, mouse and monkey MHC class I affinities for peptides of length 8-11. Nucleic Acids Res. 2008; 36(Web Server issue):W509-12. PMC: 2447772. DOI: 10.1093/nar/gkn202. View

19.

Khallouf H, Grabowska A, Riemer A . Therapeutic Vaccine Strategies against Human Papillomavirus. Vaccines (Basel). 2015; 2(2):422-62. PMC: 4494257. DOI: 10.3390/vaccines2020422. View

20.

Mkrtichyan M, Chong N, Abu Eid R, Wallecha A, Singh R, Rothman J . Anti-PD-1 antibody significantly increases therapeutic efficacy of Listeria monocytogenes (Lm)-LLO immunotherapy. J Immunother Cancer. 2014; 1:15. PMC: 4019896. DOI: 10.1186/2051-1426-1-15. View