Emilie Sandfeld

Background: The human papillomavirus (HPV), a non-enveloped double stranded DNA virus is the causative agent of many illnesses from genital warts to cervical cancer.¹ Cervical cancer, most commonly caused by HPV strains 16 and 18, is currently the 4th most common form of cancer in women throughout the world, despite having a vaccine.¹ When HPV invades cervical basal squamous epithelial cells, it can escape the innate immune system leading to progression of HPV into Cervical Intraepithelial Neoplasia (CIN).^1,2 While treatment options such as chemotherapy and radiation are available, for many women with metastatic or recurrent cervical cancer, they did not halt the growth or treat the cancer.² The newest method of immunotherapy offered a potential treatment for women with this type of cancer, specifically two drugs Pembrolizumab and Tisotumab-Vedotin.^5,6 Pembrolizumab works through blocking the binding of PD-1 and PD-L1 pathway, which normally decreases the adaptive immune system’s antigen-presenting cells and T lymphocytes so that cancer cells can continue to grow.¹ The second therapy, Tisotumab-vedotin works as an antibody drug conjugate linked with monomethyl auristatin E to target tissue factor, commonly found in solid tumors and induces cell death through disrupting microtubules, bystander toxicity, and antibody-dependent cellular phagocytosis.³

Objective: The objective of this study is to investigate the mechanisms and efficacy of Pembrolizumab and Tisotumab-vedotin in the treatment of recurrent or metastatic cancer.

Search Methods: Through the PubMed database, a search was conducted from 2017 to 2023 using the search words “cervical cancer treatment”, “cervical cancer immunotherapy”, “Pembrolizumab”, and “Tisotumab-vedotin”

Results: Preliminary studies showed evidence that PD-L1 and PD-1 expression increased as the severity of the disease increased, from HPV infection to metastatic cervical cancer.⁸ This showed that a drug blocking this pathway had potential as a therapeutic.⁸ In an ex vivo study, this drug known as Pembrolizumab, enhanced the immune system through increased proinflammatory cytokines IFN-ɣ and IL-10 in a variety of tumor cells.⁹ The other immunotherapy drug, Tisotumab-vedotin, showed ability to increase release of HMGB1, secretion of ATP, and increase ER stress.^9,10 It was also shown to induce bystander toxicity in TF+ and TF- cells and antibody-dependent cellular phagocytosis.⁹ In a clinical study, Tisotumab-vedotin had an objective response rate of 24% during an average of 4.2 months and a 6 month progression-free survival rate of 29%.⁶

Conclusions: Overall, both immunotherapy drugs have shown potential, in cell culture and clinical studies, as therapies for patients with metastatic or recurrent cervical cancer. Future studies are looking at both Tisotumab-vedotin and Pembrolizumab, as there is potential for the two immunotherapies to work better together than alone and improve the future for cervical cancer patients.¹⁰

Works Cited:

1. Balasubramaniam SD, Balakrishnan V, Oon CE, Kaur G. Key Molecular Events in Cervical Cancer Development. Medicina (Kaunas). 2019;55(7):384. Published 2019 Jul 17. doi:10.3390/medicina55070384
2. Ferrall L, Lin KY, Roden RBS, Hung CF, Wu TC. Cervical Cancer Immunotherapy: Facts and Hopes. Clin Cancer Res. 2021;27(18):4953-4973. doi:10.1158/1078-0432.CCR-20-2833
3. Olusola P, Banerjee HN, Philley JV, Dasgupta S. Human Papilloma Virus-Associated Cervical Cancer and Health Disparities. Cells. 2019;8(6):622. Published 2019 Jun 21. doi:10.3390/cells8060622
4. Johnson CA, James D, Marzan A, Armaos M. Cervical Cancer: An Overview of Pathophysiology and Management. Semin Oncol Nurs. 2019;35(2):166-174. doi:10.1016/j.soncn.2019.02.003
5. Wendel Naumann R, Leath CA 3rd. Advances in immunotherapy for cervical cancer. Curr Opin Oncol. 2020;32(5):481-487. doi:10.1097/CCO.0000000000000663
6. Hong DS, Concin N, Vergote I, et al. Tisotumab Vedotin in Previously Treated Recurrent or Metastatic Cervical Cancer. Clin Cancer Res. 2020;26(6):1220-1228. doi:10.1158/1078-0432.CCR-19-2962
7. Yang W, Lu YP, Yang YZ, Kang JR, Jin YD, Wang HW. Expressions of programmed death (PD)-1 and PD-1 ligand (PD-L1) in cervical intraepithelial neoplasia and cervical squamous cell carcinomas are of prognostic value and associated with human papillomavirus status. J Obstet Gynaecol Res. 2017;43(10):1602-1612. doi:10.1111/jog.13411
8. Roberts A, Bentley L, Tang T, et al. Ex vivo modelling of PD-1/PD-L1 immune checkpoint blockade under acute, chronic, and exhaustion-like conditions of T-cell stimulation. Sci Rep. 2021;11(1):4030. Published 2021 Feb 17. doi:10.1038/s41598-021-83612-3
9. Alley SC, Harris JR, Cao A, et al. Abstract 221: Tisotumab vedotin induces anti-tumor activity through MMAE-mediated, FC-mediated, and fab-mediated effector functions in vitro. Cancer Research. 2019;79(13_Supplement):221-221. doi:10.1158/1538-7445.am2019-221
10. Gray E, Hensley K, Allred S, et al 617 Tisotumab vedotin shows immunomodulatory activity through induction of immunogenic cell death Journal for ImmunoTherapy of Cancer 2020;8:doi: 10.1136/jitc-2020-SITC2020.0617