DRUG DEVELOPMENT - The Next Frontier in Immunotherapy for Ovarian Cancer

INTRODUCTION

Ovarian cancer is the deadliest form of gynecological can­cers, with nearly 20,000 new cases reported annually in the US alone.^1,2 While many other cancers have seen significant ad­vances over the past decade, ovarian cancer treatment has re­mained relatively unchanged. This, compounded by the frequency of late-stage detection, has created a pressing need for a powerful and safe ovarian cancer therapy. Interleukin-12 (IL-12) has long held interest for cancer researchers as a cytokine with multiple mechanisms of action. Although recombinant human IL-12 (rhIL-12) injections have produced favorable im­munological and clinical responses in patients with various ma­lignancies, treatment-related hematological and liver toxicities have limited clinical utility due to rapid increase in blood IL-12 levels causing serious systemic toxicity. To overcome the short­comings of rhIL-12 administration, IL-12-based therapy should produce IL-12 protein levels locally at the tumor site in a durable manner while maintaining a favorable safety profile.

The following will highlight a new delivery system (TheraPlas^®) being used to develop a more localized IL-12 im­munotherapy for ovarian cancer and review its promising Phase 2 results.

THE UNHARNESSED POTENTIAL OF INTERLEUKIN-12

Cytokines, like IL-12, are a crucial class of proteins that allow cells of the immune system to communicate with each other and with other cells in the body. Interferon, chemokines, and inter­leukins are all part of this massive family of messenger proteins produced by both immune and non-immune cells. These protein-based signals coordinate cellular processes during day-to-day homeostasis, as well as coordinate immune efforts during various disease states.

Due to their central role in important signaling pathways, cy­tokines have long been studied and harnessed for their therapeu­tic potential. Many cytokine-based immunotherapies exist, and they are a particularly prevalent form of cancer treatment. These immunotherapies aim to boost or redirect the immune response and kickstart the body’s defense system into removing cancerous cells.

IL-12 has been heavily explored as an immunotherapy op­tion based on its proven anti-cancer activity. IL-12 is a signaling powerhouse, bridging the gap between our innate and adaptive immune responses by recruiting important cancer-fighting cells and boosting anti-tumor activities. For example, IL-12 has been shown to enhance the growth and cytotoxicity of natural killer cells and T-cells, two cell types capable of destroying tumor cells. IL-12 directly boosts production of IFN-g, another cancer-fighting cytokine and master immune stimulator. IL-12 also has anti-an­giogenesis properties that can inhibit blood vessel formation in new tumors, enhances antigen presentation, and plays a role in increasing antibody production.

Given this impressive resume, IL-12 is a prime candidate for cancer immunother­apy treatments, and animal models further support the anti-cancer abilities of IL-12. For treatment of both solid tumors and blood cancers, administering IL-12 in mice was a highly effective anti-cancer therapy.³ Notably, IL-12 treatment was even benefi­cial when given in combination with chemotherapy, a particularly interesting finding given that chemotherapy can pre­vent an effective immune response in some cases.³

However, these promising preclinical results have not yet been successfully transferred to the clinic. In the 1990s and 2000s, many IL-12 trials were piloted, using a variety of therapeutic approaches and targeting a diverse set of cancers that included breast cancer, melanoma, lym­phomas and others.³ IL-12 was injected subcutaneously, intravenously, in combina­tion with other therapies, and across a broad range of dosages. Unfortunately, al­though supported by the best efforts of many experienced research teams and cli­nicians, treatment with IL-12 was not the rousing success that preclinical trials sug­gested it could be.

It was found that IL-12 treatments were less potent than predicted as the tumor microenvironment was preventing IL-12 therapies from being highly effica­cious.³ Human tumors are more heteroge­neous than mouse tumors, which makes it harder for the immune system to effectively recognize the entirety of the cancer. This also contributes to a more robust tumor microenvironment that acts as a sort of shield for the invasive cancer. This mi­croenvironment can effectively dampen the body’s immune response at a local level and is a major contributor to the per­sistence and progression of many cancers.

Another concern was that systemic distribution of IL-12 produced unpleasant and occasionally dangerous side effects. The most common side effects were flu-like symptoms (headache, chills, fatigue), but there were also cases of cytokine re­lease syndrome, otherwise known as a “cytokine storm,” that occurs when the body releases too many cytokines too quickly. This can result in dangerously high fevers, generalized inflammation, and life-threatening organ failure in more extreme cases.

Fortunately, the tumor microenviron­ment is not impenetrable. More recent studies of IL-12 as an anti-cancer agent have explored strategies to overwhelm the local tumor microenvironment with a more targeted application of IL-12. More fo­cused approaches to IL-12 immunother­apy would presumably reduce unwanted side effects as well. Early results are highly encouraging, providing hope that the promise of IL-12 may soon be realized.

NEW HOPE FOR OVARIAN CANCER PATIENTS

Treatment of ovarian cancer is one field that could particularly benefit from a safer and more efficacious IL-12 therapy. Ovarian cancer is the second most com­mon gynecologic cancer in the US and the deadliest cancer of the female reproduc­tive system.² This is due in part to the dif­ficulty of early detection. Early symptoms are often subtle, and 80% of diagnoses occur as late-stage cancers (stage III/IV).⁴ Within the US, approximately 13,000 peo­ple lose the fight to ovarian cancer each year, making it the fifth leading cause of death in women and highlighting the need for improved treatment regimens.^1,2

The current standard of care is plat­inum-based chemotherapy and surgical intervention, depending on the state of disease progression. Platinum-based chemotherapy drugs rely on platinum ions to cause DNA damage within rapidly di­viding cancer cells. This systemic therapy can be combined with a procedure known as tumor debulking surgery, in which tu­mors are removed from the patient to min­imize the number of cancerous cells. Ovarian cancer has not seen the same therapeutic advancements as other cancers; however, and this standard treatment approach has not evolved much since the 1960s. This has unfortunately left overall survival rates quite low, with 49% of ovar­ian cancer patients, including all disease stages dying within 5 years of diagnosis.^1,2

Fortunately, we may be entering a new era in the treatment of ovarian cancer. For instance, a new class of drugs called PARP inhibitors represents a promising step forward. PARP inhibitors work by halt­ing single-strand DNA repair, forcing cells to rely on a form of DNA repair known as homologous recombination. A common mutation found in both breast and ovarian cancer cells (BRCA mutations) often results in inefficient homologous recombination, preventing cancer cells from repairing their DNA and eventually killing the cell.

Three PARP inhibitors were approved for use against ovarian cancer between 2014 and 2017: olaparib, rucaparib, and niraparib. Given that both platinum-based chemotherapy and PARP inhibitors rely on interfering with cancer cell DNA, one of the primary use cases for these new drugs is patients who have responded positively to platinum-based chemotherapies. This approach, called maintenance treatment, focuses on preventing ovarian cancer from growing or recurring. The results have been promising, with progression-free sur­vival rates improving by around 6 months (or longer in selected subgroups) in people being treated with PARP inhibitors and may also produce a survival benefit.

Based on this success, some PARP inhibitors are now approved for mainte­nance in patients whose tumors have re­sponded to initial chemotherapy/surgery; that is, using PARP inhibitors after the initial therapy for newly diagnosed patients. However, the effectiveness of PARP in­hibitors relies on cancer cells being defi­cient in homologous repair, which is not always the case. There are also concerns that PARP inhibitors may increase a pa­tient’s risk for blood cancers, similar to the risks associated with chemotherapy treat­ment. Thus, while PARP inhibitors are a much-needed advancement in the treat­ment of ovarian cancers, the majority of patients with advanced ovarian cancer will still suffer recurrence after a few years. Ad­ditional treatment options are sorely needed.

IMNN-001: ENCOURAGING PROGRESS FOR A NOVEL IL-12 IMMUNOTHERAPY

Recently, a new IL-12 immunotherapy, IMNN-001, has shown promising poten­tial for ovarian cancer treatment. Initial forays into IL-12 immunotherapies em­phasized the need for local delivery of IL-12 at the tumor site to avoid cytokine release syndrome and to achieve higher tumor distribution in the immunosuppres­sive tumor microenvironment. IMNN-001 was designed based on a novel technol­ogy platform known as TheraPlas that has provided the technological tools to do just that.

TheraPlas is a non-viral nanoparticle delivery system that can be used to engi­neer cells with anti-cancer nucleic acid-based therapies. In early clinical research for IMNN-001, TheraPlas was used to de­liver a DNA plasmid vector encoding IL-12. The TheraPlas delivery system protects the IL-12 plasmid from degradation fol­lowing injection and enhances cellular up­take of the plasmid for a more efficient gene transfer. This results in the robust and durable production of IL-12 at the site of the tumor. As cells secrete IL-12 into their environment, a more localized concentra­tion of IL-12 is achieved. This focused de­livery of IL-12 reduces the risk of serious systemic toxicity, including cytokine storms, and helps overwhelm the tumor microen­vironment with these powerful cytokine proteins.

This investigational immunotherapy recently completed a randomized and controlled Phase 2 clinical trial (OVATION 2) in which it demonstrated a favorable safety profile and quantifiable improve­ments in patient outcomes, when compared head-to-head with chemother­apy/surgery.^5,6 In this trial, the treatment group received IMNN-001 alongside the standard of care platinum-based chemotherapy, while the control group re­ceived standard of care alone. The treat­ment group achieved a 13-month increase in median overall survival compared to the standard of care. This study also saw a 27% increase in progression-free survival rates, an improvement of approximately 3 months.

This is the first immunotherapy treat­ment to achieve clinically meaningful im­provements in both progression-free and overall survival rates, when used as a first-line treatment (in conjunction with chemotherapy) for newly diagnosed ad­vanced ovarian cancer patients. A closer look at the data is even more encourag­ing. Women who received more treatment cycles of IMNN-001 showed an even more significant improvement in overall survival (close to 16 months). The addition of PARP inhibitors to IMNN-001 further enhanced patient outcomes, indicating a positive outlook for combinational treatments in­volving these two new therapies. Through­out the entirety of the study, including an extended monitoring period, there have been no reports of serious immune-related adverse events and the safety profile for this IL-12-based immunotherapy remains encouraging.

The TheraPlas delivery system, which is independent of a viral vector and a de­vice, may finally allow researchers and cli­nicians to harness the cancer-fighting power of IL-12. While further investigation is needed, such exciting results are a wel­come reprieve to those fighting ovarian cancers or concerned about their genetic risk of developing it. A Phase 3 clinical trial of IMNN-001 is scheduled to begin this year and will continue to explore the safety and efficacy of the first immunotherapy shown to improve survival rates for ovar­ian cancer.

These early clinical results demon­strate that TheraPlas is well-tolerated and effective at delivering IL-12 to the peri­toneal cavity, inviting exploration of this delivery system for use in other cancers, in­cluding colorectal, uterine, and pancreatic. Researchers have demonstrated anti-can­cer application of TheraPlas technology in animal models of pancreatic and colorec­tal cancer metastasized into abdominal cavities.

SUMMARY

Ovarian cancer is a daunting disease that has long stumped researchers’ best efforts to control and cure it, especially in late stages. The therapeutic application of IL-12 has been similarly difficult due to se­rious systemic toxicity and low bioavailabil­ity at the tumor site, resisting our best efforts to wrestle it into a functional im­munotherapy, despite the enormous po­tential it displays in early clinical trials and animal studies. The TheraPlas delivery sys­tem, due to its ability to produce IL-12 lo­cally at the tumor site in a durable manner without causing serious systemic toxicity typically associated with the delivery of re­combinant IL-12, has found a way to kill two birds with one stone, advancing IL-12 immunotherapies and extending the lives of ovarian cancer patients and survivors. While the full safety and efficacy profile of IMNN-001 must still be established in Phase 3, the first two phases of this clinical trial encourage cautious optimism that a better standard of care for ovarian cancer is possible, and that we may be able to apply these lessons to other cancers as well.

REFERENCES

1. USCS Data Visualizations – CDC. Accessed March 14, 2025. https://gis.cdc.gov/Can­cer/USCS/#/AtAGlance/.
2. Cancer Statistics Center – American Cancer Society. Accessed March 14, 2025. https://cancerstatisticscenter.cancer.org/.
3. Lasek W, Zagożdżon R, Jakobisiak M. In­terleukin 12: still a promising candidate for tumor immunotherapy? Cancer Immunol Immunother. 2014;63(5):419-435. doi:10.1007/s00262-014-1523-1.
4. Torre LA, Trabert B, DeSantis CE, et al. Ovarian cancer statistics, 2018. CA Can­cer J Clin. 2018;68(4):284-296. doi:10.3322/caac.21456.
5. IMUNON Announces Continued Strong Improvement in Overall Survival Data from Randomized Phase 2 OVATION 2 Study of IMNN-001 | IMUNON, Inc. Accessed March 14, 2025. https://investors.imunon.com/news-re­leases/news-release-details/imunon-an­nounces-continued-strong-improvement-overall-survival.
6. IMUNON Presents Positive Data from Phase 2 OVATION 2 Clinical Trial of IMNN-001 in Advanced Ovarian Cancer at SITC 39th Annual Meeting | IMUNON, Inc. Accessed March 14, 2025. https://in­vestors.imunon.com/news-releases/news-release-details/imunon-presents-positive-data-phase-2-ovation-2-clinical-trial.

Khursheed Anwer, PhD, MBA, is Executive Vice President and Chief Science Officer of IMUNON, Inc. He was previously President and Chief Science Officer of EGEN, Inc., a position he held since 2009, before the company was acquired by IMUNON in June 2014. Dr. Anwer joined EGEN, Inc. in July 2002 as Vice President of Research and Development and directed the company’s clinical and research and development functions throughout his tenure at the company. He was previously Director of Pre-Clinical Development at Valentis, Inc. From 1993 to 1999, he served in several positions at GeneMedicine, Inc., where he led several research projects in the area of non-viral gene therapy. Dr. Anwer has a PhD in physiology/pharmacology from Ohio University and received postdoctoral training from the University of Texas Health Science Center at Houston. He has authored more than 40 publications in the area of non-viral gene therapy, resulting from his active career in research and development. Dr. Anwer has served as an adjunct faculty member in the Biology Department at the University of Alabama in Huntsville and a board member of the University of Alabama Business School, STEP.

Douglas V. Faller, MD, PhD, is Chief Medical Officer of IMUNON, Inc. Dr. Faller has more than 30 years of experience at biotechnology and pharmaceutical companies leading strategies across discovery, preclinical, clinical and regulatory stages of small molecule development in several therapeutic areas including oncology, immunology and hematology. He also brings more than 25 years of experience in academic clinical and laboratory research settings with a focus on drug discovery and development, oncology and hematology, and cell and molecular biology. Dr. Faller most recently served as Chief Medical Officer at Skyhawk Therapeutics, where he was responsible for global clinical and regulatory development of novel small molecule RNA-splicing modifiers for the treatment of hematological and solid tumors and rare neurological diseases. Before that, he served as Chief Medical Officer at Oryzon Genomics, Inc. Previously, he worked at Takeda for more than five years, most recently serving as Executive Medical Director where he led the development of multiple early and late-stage therapies including small molecule and CAR-T programs for leukemias and lymphomas, and solid tumor programs including in gynecologic oncology. Dr. Faller received an MD from Harvard Medical School and a PhD and BS from the Massachusetts Institute of Technology. He was professor of medicine at Harvard Medical School, and subsequently he founded and served as first director of Boston University Comprehensive Cancer Center where he was also Grunebaum Professor for Cancer Research and professor of medicine, biochemistry, pediatrics, microbiology, pathology and laboratory medicine. Dr. Faller is the scientific founder of multiple biotechnology and pharmaceutical companies.