Harnessing IL-12: Immunotherapy research advances may enhance survival rates for women with ovarian cancer

While there have been many significant advances in healthcare in the past 25 years, including new treatments for cancer recurrence, more effective disease maintenance strategies, more precise and easier to use diagnostic tools, and even advances in palliative care, the standards of care in upfront ovarian cancer treatment have not kept pace.

One reason is the fact that much research related to ovarian cancer has focused on strategies combining chemotherapy with immunotherapies such as checkpoint inhibitors, due to the limitations experienced with prior research utilising interleukin-12 (IL-12), which is often considered to be one of the “holy grails” in cancer immunotherapy.

IL-12 is a powerful cytokine, a type of protein that acts as a chemical messenger, that plays a key role in initiating the body’s natural immune response. Several studies of IL-12 immunotherapies have shown encouraging results in animal models, but in humans they have been associated with only modest anti-tumour effects and a range of dose-limiting side effects, including systemic flu-like symptoms, hepatotoxicity, and cytokine release syndrome.^1,2

Most researchers believe that these side effects are caused by IL-12 delivery methods that are designed to provide high therapeutic doses to the blood stream to elicit large systemic responses. The risks associated with these therapies have severely limited progress in the development of novel IL-12 immunotherapies for ovarian cancer and for some other types of cancer.

While oncologists accept the current standard of care because there are no alternatives, most agree that there is an urgent need to improve strategies to prolong survival, especially for all patients in a first line setting, including patients who are homologous recombination proficient (HRP). A new option that could address the limitations of existing therapies would represent a major advance in care for thousands of women, potentially including those with advanced stages of disease.

A brief history of IL-12 immunotherapy

Therapies designed to deliver IL-12 have been a promising focus in cancer immunotherapy research since the cytokine was first discovered in 1989.³ Extensive research in preclinical cancer models has validated its potential to activate immune cells that form the tumor microenvironment, such as natural killer cells and T lymphocytes, establishing a link between innate and adaptive immunity by stimulating production of interferon-γ – a cytokine that coordinates the body’s natural mechanisms of anti-tumour defense.⁴

IL-12 has also been shown to reduce or delay tumour growth and increase survival using multiple delivery methods, including systemic intravenous, intraperitoneal, subcutaneous, and intra-tumoural delivery.³ The potent anti-tumour activity has the potential for significant efficacy benefit as a monotherapy, but the advantageous pharmacokinetic profile also makes IL-12 drugs ideal candidates for combination therapy approaches to increase the immunogenicity of tumours.³ Several preclinical studies have demonstrated that IL-12 immunotherapies used in combination with chemotherapies, cytokines, monoclonal antibodies, radiotherapies, and other therapeutic modalities resulted in more robust anti-tumour responses compared to monotherapy approaches.⁴

Recognising the tremendous potential to deliver a historic advance in patient care, in recent years researchers have focused on strategies to harness the robust anti-tumour response of IL-12 therapies without causing toxic side effects.

Targeting delivery at the tumour site

In the last few years, researchers have made important progress in identifying novel ways to deliver IL-12 therapies. One such promising approach currently being studied in clinical trials is designed to help the body’s immune system fight cancer at the tumour site without the use of a virus as the IL-12 delivery tool. IMUNON’s TheraPlas is a non-viral delivery system that can support development of a range of immunotherapies and other anti-cancer nucleic acid-based therapies. For example, using this advanced technology, researchers developed an IL-12 immunotherapy called IMNN-001 that uses a DNA plasmid vector encased in a nanoparticle delivery system to deliver IL-12 locally to the tumour micro-environment, initially targeting advanced ovarian cancer.

A plasmid delivery system protects DNA from degradation and enhances cellular uptake without excessive breakdown. This method increases the durability of IL-12, extending its impact, and targets immune cells within a tumour and adjacent lymph nodes while avoiding circulating lymphocytes. By focusing on the local tumour environment and optimising IL-12 delivery, there is significant potential to drive robust anti-tumour responses while substantially reducing the risk of toxic adverse events for patients.

Addressing the unmet needs in ovarian cancer

Ovarian cancer is the second deadliest gynaecologic malignancy.⁵ Most treatments are administered in women in later stages of disease progression when the potential for positive efficacy benefit is diminished. Results thus far indicate that novel strategies in the delivery of IL-12 immunotherapies, including using non-viral DNA plasmid delivery methods to target the tumour microenvironment, may be able to significantly improve outcomes for more women with ovarian cancer. These approaches could lead to the development of IL-12 immunotherapies that have important implications for the treatment of many different types of cancer in the years ahead.

About the authors

Stacy R. Lindborg, PhD, was appointed president and chief executive officer of IMUNON, Inc. in May 2024. She has served on the company’s board of directors since June 2021. Dr Lindborg has nearly 30 years of pharmaceutical and biotechnology industry experience with a particular focus on R&D, regulatory affairs, executive management, and strategy development. She has designed, hired, and led global teams, guiding long-term vision for growth through analytics and stimulating innovative development platforms to increase productivity.

Premal H. Thaker, MD, is interim chief of gynaecologic oncology, David & Lynn Mutch Distinguished Professor of Obstetrics and Gynaecology, and director of gynaecologic oncology clinical research at Washington University School of Medicine.