Deep within the abdomen, on either side of the uterus, sit the ovaries. Due to their small size and location, if cancer develops there, it is very difficult to detect — often leading to a diagnosis only at advanced stages. This makes ovarian cancer the deadliest gynecological cancer; more than 60 percent of women die within five years of a late-stage diagnosis (1).

Immune cells in the region around the tumor, however, play a key role in the cancer’s progression.

“Ovarian cancer is just like a lot of cancers: The better your immune system is, hopefully the better it can take care of the cancer,” said Premal Thaker, a gynecologic oncology clinician and researcher at Washington University in St. Louis. Researchers have seen that when immune cells do manage to infiltrate the ovarian tumor microenvironment, patients have better outcomes (2).

Giorgio Valabrega, an ovarian cancer researcher at the University of Turin, explained that this finding encouraged multiple research groups to develop immunotherapies for ovarian cancer. The majority of them were immune checkpoint inhibitors, which aid the immune system by helping T cells recognize tumor cells that try to evade detection.

The initial excitement around these immunotherapies for ovarian cancer, however, has dimmed. Clinical trial after clinical trial with these drugs showed little to no improvement for patients over the standard of care, which for late-stage ovarian cancer is first chemotherapy to shrink the tumor, followed by surgery to remove as much of the tumor as possible, and then another round of chemotherapy to treat any remaining cancer cells (3).

But now, researchers at Imunon, a biotechnology company developing DNA-based immunotherapies, may have found a way forward with their new drug IMNN-001. It harnesses interleukin-12 (IL-12), a powerful immune stimulator, to help patients’ immune systems fight against advanced ovarian cancer. With positive Phase 2 data, the Imunon team thinks that they may even have a new first-line treatment for ovarian cancer on their hands.

“We really haven't seen a change to the standard of care, to first-line treatment, for 25 years,” said Stacy Lindborg, the President and Chief Executive Officer of Imunon. “For no progress for this long, it leaves us with a lot of hope.”

Harness IL-12, gain the immune system

For years, scientists have known that IL-12 is a powerhouse when it comes to whipping up a strong immune response against cancer (4). It activates tumor-fighting cytotoxic CD8+ T cells and natural killer cells, promotes the production of interferon gamma to decrease the tumor’s blood supply, inhibits regulatory T cells that suppress the immune response, and leads to the production of other immunostimulatory molecules (5).

“It just has this multi-prong attack,” said Thaker, adding that it has “different ways of augmenting the immune system, and that's really critical.”

Despite its cancer-fighting strengths, there are currently no IL-12-based therapies. The problem, it turned out, was that IL-12 is a little too strong. While IL-12 led to positive responses in patients in clinical trials, high systemic levels of IL-12 also caused intolerable liver and hematological toxicities (6).

“A lot of the promise of IL-12 … was very well recognized and very well appreciated, also amongst Big Pharma, but nobody had figured out how to safely deliver it,” said Lindborg.

During this time, however, researchers led by Khursheed Anwer, now the Executive Vice President and Chief Science Officer of Imunon, were developing a solution. Rather than deliver IL-12 systemically, Anwer and his team formulated a DNA plasmid encoding the human IL-12 gene into a nanoparticle made of a synthetic lipopolymer (7). This gene therapy was originally named GEN-1, but Imunon has now renamed it to IMNN-001.

“It's a very unique gene therapy in the sense that all of the approved gene therapies are viral. This is a non-viral gene therapy,” said Lindborg. “These DNA plasmids are encoded to basically instruct the body to produce this immune response.”

“A lot of the promise of IL-12 … was very well recognized and very well appreciated, also amongst Big Pharma, but nobody had figured out how to safely deliver it.” 
- Stacy Lindborg, Imunon

In a 2009 study, the researchers injected the therapy into the peritoneal cavity in the abdomens of mice, and they saw significant local IL-12 production that persisted there for several days (8). They then combined IMNN-001 with chemotherapy and saw improved survival of the animals.

Valabrega, who is not associated with Imunon, thought the strategy of using IL-12 to stimulate the immune system against the tumor was interesting. “When ovarian cancer progresses during platinum-based therapies, it becomes more cold, using an immunological term. And so, the idea of stimulating the immune system with IL-12 might be maybe a good idea, especially in association with chemotherapy.”

With the promising results in mice, the Imunon team initiated a non-randomized, open-label Phase 1b trial called OVATION 1 in 2015 to evaluate the drug in people with advanced epithelial ovarian cancer.

One hurdle they had to overcome was how to administer the drug to patients. Nowadays, people typically receive cancer treatments through an intravenous infusion or a pill, but the Imunon team needed to deliver IMNN-001 directly into the peritoneal space where the ovarian tumor resided. They decided on an approved, but older method of chemotherapy delivery: the catheter.

“Chemotherapy used to be delivered into [the] peritoneal cavity and through a catheter,” said Lindborg. “It was very hard for patients to tolerate, which is why it went kind of out of vogue.” But, she added, “At the end of the day — and I've heard this in conversations at ASCO [American Society of Clinical Oncology Annual Meeting] this year with clinicians — nobody cares about route of delivery when you have a large effect.”

In the Phase 1b trial, 18 patients with either stage 3 or stage 4 ovarian cancer received both IMNN-001 and chemotherapy (9). The researchers didn’t see any dose-related toxicities and found that IL-12 remained in the peritoneal space.

“[We] saw very promising results,” said Thaker, who was the Washington University principal investigator for the clinical trial. “The immune system was being targeted, not systemically in the blood, but really in the tumor microenvironment.”

With increased immune cell activity around the ovarian tumor along with signs of decreased immunosuppression, the team embarked on a larger Phase 2 study called OVATION 2 in 2018.

Evolving the standard of care

Just as in the Phase 1 trial, the Imunon team administered IMNN-001 with the standard of care chemotherapy or only the standard of care to 112 patients with advanced ovarian cancer. When the researchers released topline results from this trial in July 2024, they saw an 11.1 month increase in median overall survival for people who received the combination IMNN-001 and chemotherapy treatment compared to just chemotherapy alone.

“When you tell patients you have about almost an 11-month improvement, that's significant in life. That's almost close to another year of celebrations, birthdays, being around,” said Thaker. “We haven't seen that to date yet in upfront, overall survival.”

Then, in December 2024, the Imunon team released updated results from OVATION 2 that showed that the median overall survival with IMNN-001 plus chemotherapy has now increased to 13 months longer than the standard of care.

After receiving IMNN-001 and chemotherapy, some patients also received poly(ADP-ribose) polymerase (PARP) inhibitors as a maintenance therapy if they happened to have BRCA-mutations.

“When this trial was originally designed, PARP inhibitors were not standard of care maintenance,” said Thaker. “A lot of times trials are written a couple years in advance of being implemented, or as they're implemented, things change.”

To the researchers’ surprise, the patients who received PARP inhibitors after the experimental therapy overall had even longer survival. As of a November 2024 presentation at the Society of Immunotherapy of Cancer Annual Meeting, the median overall survival point  in this experimental group had not yet been met, meaning that more than half of the patients in that subgroup were still alive when the data were collected. The median overall survival for the control arm was 37.1 months.

“We're really also interested and intrigued by this improvement that we're seeing with the use of IMNN-001 with PARP inhibitors subsequently,” said Thaker. “There's a lot of data emerging about how immunotherapy compounds given early can sort of change their trajectory downstream, because the immune system is also, I'd say, not the fastest system. It needs education over time. We give it to you, and it still probably is working.”

Valabrega was also eager to learn more about how the ovarian tumor microenvironment changed in patients who received IMNN-001. “What I would like to see is a deep characterization of the patients who will derive a response,” he said. “It would be very interesting to characterize, from an immunological point of view, the tumor before and after the treatment.”

Based on the positive results reported so far, the Imunon team plan to start a Phase 3 pivotal trial testing IMNN-001 in more advanced stage ovarian cancer patients in the first quarter of 2025.

“I've been in the industry for 30 years, and I've been a part of developing products that have been revolutionary. But it's not that often that you can evolve the standard of care.” 
- Stacy Lindborg, Imunon

“There has never been a trial that has shown a benefit in overall survival … and in front line therapy, we are the only trial that has ever shown a benefit,” said Lindborg. “If we replicate these results in Phase 3, this will be transformative to the standard of care and offers just amazing hope for patients.”

Since a combination therapy of IMNN-001 plus chemotherapy would be given to patients who have not received any prior treatment — in an effort to stimulate their immune systems to their fullest extent — it would be a new first-line treatment for ovarian cancer.

“I've been in the industry for 30 years, and I've been a part of developing products that have been revolutionary. But it's not that often that you can evolve the standard of care,” said Lindborg. “What this could mean for women with ovarian cancer is just incredibly motivating.”

References

1. Cancer Research UK. Survival for ovarian cancer. (2024).
2. Hwang, W.T. et al.  Prognostic significance of tumor-infiltrating T cells in ovarian cancer: A meta-analysis. Gynecol Oncol  124, 192-198 (2012).
3. Ghisoni, E., Imbimbo, M., Zimmermann, S., & Valabrega, G. Ovarian Cancer Immunotherapy: Turning up the Heat. Int J Mol Sci  20, 2927 (2019).
4. Kobayashi, M. et al.  Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med  170, 827-845 (1989).
5. Tugues, S. et al.  New insights into IL-12-mediated tumor suppression. Cell Death Differ  22, 237-246 (2015).
6. Jia, Z. et al.  IL12 immune therapy clinical trial review: Novel strategies for avoiding CRS-associated cytokines.Front Immunol  13, 952231 (2022).
7. Thaker, P.H., Borys, N., Fewell, J., & Anwer, K. GEN-1 immunotherapy for the treatment of ovarian cancer. Future Oncol  15, 421-438 (2019).
8. Fewell, J.G. et al.  Treatment of disseminated ovarian cancer using nonviral interleukin-12 gene therapy delivered intraperitoneally. J Gene Med  11, 718-728 (2009).
9. Thaker, P.H. et al.  GEN-1 in Combination with Neoadjuvant Chemotherapy for Patients with Advanced Epithelial Ovarian Cancer: A Phase I Dose-escalation Study. Clin Cancer Res  27, 5536-5545 (2021).