There Is a Need for Better CIN Therapies to Prevent Cervical Cancer

January was cervical health awareness month, with many health organizations publicizing messages promoting prevention and screening for cervical cancer. With cervical cancer ranking as the fourth most common cancer in women, responsible for more than 300,000 deaths annually, this is an important global health issue.¹ However, despite advancements in prevention, such as human papillomavirus (HPV) vaccination, United States incidence rates for cervical cancer in young adults have increased by 1% to 2% annually between 2015 and 2019.² Luckily, regular testing is highly effective at detecting precancerous growth of cells on the cervix—known as cervical intraepithelial neoplasia (CIN) or cervical dysplasia—prior to its development into cancer. However, current methods of treating CIN are invasive and carry the risk of lasting side effects and recurrence. This article explores the need for better ways of addressing CIN, along with therapies currently under development, which hold the potential to transform CIN treatment paradigms.

The Current State of CIN

The root cause for the majority of cervical cancer cases—more than 90%—is an HPV infection.³ While HPV has many variants, HPV-16 and HPV-18 are those at the highest risk of causing CIN and, subsequently, cancer. These variants express E6 and E7 oncoproteins, which interfere with the cells’ ability to respond to DNA damage with apoptosis, while also promoting unregulated cell division. The resulting abnormal cell growth on the surface of the cervix is a defining characteristic of CIN, which can then be graded on a scale from 1 to 3, depending on the proportion of the tissue exhibiting abnormalities. Patients with CIN-2 and CIN-3 are at a high risk for developing cancer, making it imperative that they receive appropriate treatment.

However, current treatment is primarily centered on the surgical removal of these precancerous lesions, such as loop electrosurgical excision procedure (LEEP), or laser-, thermal-, or cryo-ablation. These treatments not only are invasive, but also can be accompanied by lasting side effects, including pregnancies with increased risk for premature birth and low birth weight.⁴ Further, surgical removal does not address the underlying HPV, and surgery may not completely remove all abnormal cells, leaving patients with a high risk of CIN recurrence.

Finding Alternatives to Surgery

Many researchers have identified the pressing need for alternative methods of treating CIN before it becomes cancerous. A variety of approaches are being investigated and developed, each with its own possibilities and limitations relative to the current standard of care.

Adjuvant Vaccination

A natural extension of already established HPV vaccines, adjuvant vaccination can be employed alongside surgically managed CIN for individuals who were not previously vaccinated. Compared to surgery alone, the addition of adjuvant vaccination may reduce the risk of recurrence by as much as 65%, particularly for HPV genotypes 16 and 18.5 However, adjuvant vaccination is not a true alternative to surgery, and, as a result, does not alleviate many of the problems associated with it, such as its invasiveness and side effects.

Topical Treatments

To replace surgery entirely, some are exploring topical methods. One of these is imiquimod, a cream that is currently used to treat external genital or anal warts caused by HPV, as well as superficial basal cell carcinoma. Imiquimod stimulates the local immune response on the cervix by increasing antigen presentation, which, in turn, stimulates the secretion of pro-inflammatory cytokines. It also stimulates the immune system to specifically target HPV-infected cells.

Current studies show that use of imiquimod results in a 55% histologic regression rate, compared to placebo—however, it is not as effective as LEEP for high-grade CIN.⁶ What’s more, a 16-week treatment duration, along with uncomfortable side effects, such as pain and redness at the site and flu-like symptoms, makes this treatment option a less than ideal alternative to surgery. Nevertheless, imiquimod may be a beneficial option for patients who wish to become pregnant, or who have recurrent CIN and wish to avoid a repeated surgery.

There are additional ongoing clinical trials investigating the use of topical imiquimod in combination with fluorouracil, another topical treatment used for some types of cancer and HPV-caused lesions. Fluorouracil has shown promise independently in small studies, though some concentrations and treatment frequencies have been associated with adverse effects, such as burning, pain, and chronic ulceration. While feasibility trials have shown preliminary evidence of the efficacy of combining it with imiquimod, further studies will be necessary to determine the extent of the combination’s ability to mitigate CIN.⁷

mRNA Therapies

In the last several years, mRNA has very notably entered the medical field as a powerful method of treatment. This also applies to HPV-driven tumors and lesions, such as CIN, with several drug developers, including BioNTech and Nutcracker Therapeutics, working to create mRNA-based therapies that can prime the immune system to respond to HPV. A promising approach is to introduce an mRNA vaccine that generates T-cell based immune responses against E6 and E7, the key oncoproteins expressed by high-risk HPV. Unlike existing prophylactic vaccines such as HPV 9-valent vaccine, recombinant (Gardasil; Merck) that provide protection to HPV prior to infection, mRNA vaccines can have a therapeutic effect, allowing them to help clear the HPV virus in infected patients.

Multimodal mRNA therapeutics—those with multiple mechanisms of action—expand the available ‘toolkit’ to address CIN. In addition to the vaccine component, a multimodal therapy, such as preclinical candidate NTX-250 (Nutcracker Therapeutics), introduces immunostimulatory proteins that activate the local cellular environment to generate stronger and more durable immune responses against the virus.

The use of mRNA in CIN has yet to move past clinical trials. However, it has the potential to remedy the abnormal growth of cells, in addition to clearing the underlying HPV infection, without the same level of invasiveness and risk of surgery.

The use of mRNA in CIN has yet to move past clinical trials. Image Credit: © Saiful52 - stock.adobe.com

Progressing to Cervical Cancer

Even as we make progress in treating CIN, so too must we consider its counterpart: cervical cancer. The current therapies for cervical cancer are similarly limited, with surgery, chemotherapy, and radiation being the primary methods of treatment — with just one immunotherapy, pembrolizumab (Keytruda; Merck), approved for use.

This is a far cry from the wide variety of advanced therapies (such monoclonal antibodies, T-cell engagers, cell therapies, and antibody-drug conjugates) available for other forms of cancer. However, some drug developers—such as Repertoire Immune Medicines and Precigen—are exploring new therapeutic approaches in this space, including T-cell therapies and the combination of HPV vaccines with immune checkpoint inhibitors.

At the same time, some mRNA treatments for CIN may also have applications in cervical cancer through the same mechanism of action. In fact, the immunostimulatory proteins found in some multimodal therapies under development, such as NTX-250, can reprogram the tumor microenvironment by activating innate immune cells and reversing tumor driven immunosuppression, making it easier for T-cells to infiltrate and combat tumor cells.

Although a large number of promising new treatments for CIN and cervical cancer are still under development, filling this gap in care standards has clearly become a priority for many researchers in the women’s health care field. The next few years should see drastic changes in CIN/Cervical cancer treatment options, which, in addition to better prevention and screening strategies, will be of great benefit to the 600,000 women who are diagnosed each year.

About the Authors

Sam Deutsch, PhD, is chief scientific officer at Nutcracker Therapeutics, leading biological research and development. Sam orchestrates the advancements of the company’s therapeutics pipeline through close interactions between internal R&D, scientific advisors and clinical collaborators. Prior to Nutcracker Therapeutics, Sam led the DNA synthesis platform at the Joint Genome Institute, part of Lawrence Berkeley National Laboratory. Sam’s experience also includes research in molecular hematology at the Geneva University Hospital, and cancer genomics at the World Health Organization.

Nicole Fay, PhD, is director of Pharmacology at Nutcracker Therapeutics, where she leads the product development of NTX-250, the company’s mRNA therapeutic candidate for cervical intraepithelial neoplasia. Nicole has more than 18 years of experience in the development of biologics, mRNA, and gene therapy for various indications, including oncology, autoimmune diseases, and metabolic diseases.

REFERENCES

1. WHO. Cervical cancer. WHO website. March 5, 2024. Accessed January 23, 2024. https://www.who.int/news-room/fact-sheets/detail/cervical-cancer

2. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024 [published correction appears in CA Cancer J Clin. 2024 Mar-Apr;74(2):203]. CA Cancer J Clin. 2024;74(1):12-49. doi:10.3322/caac.21820

3. CDC. HPV Can Cause Certain Cancers in Men and Women. Centers for Disease Control and Prevention. Published March 17, 2023. Accessed January 23, 2024. https://www.cdc.gov/hpv/parents/cancer.html

4. Kyrgiou M, Athanasiou A, Kalliala IEJ, et al. Obstetric outcomes after conservative treatment for cervical intraepithelial lesions and early invasive disease. Cochrane Database Syst Rev. 2017;11(11):CD012847. doi:10.1002/14651858.CD012847

5. Di Donato V, Caruso G, Petrillo M, et al. Adjuvant HPV Vaccination to Prevent Recurrent Cervical Dysplasia after Surgical Treatment: A Meta-Analysis. Vaccines. 2021;9(5):410. doi:10.3390/vaccines9050410

6. Van De Sande AJM, Kengsakul M, Koeneman MM, et al. The efficacy of topical imiquimod in high‐grade cervical intraepithelial neoplasia: A systematic review and meta‐analysis. Intl J Gynecology & Obste. 2024;164(1):66-74. doi:10.1002/ijgo.14953

7. Desravines N, Hsu CH, Mohnot S, et al. Feasibility of 5-fluorouracil and imiquimod for the topical treatment of cervical intraepithelial neoplasias (CIN) 2/3. Int J Gynaecol Obstet. 2023;163(3):862-867. doi:10.1002/ijgo.14983