Targeting IL-12 Safely With Intraperitoneal Therapy Represents Key Step Forward in Ovarian Cancer

Although targeting IL-12 has been difficult historically, an IL-12–targeted immunotherapy has shown encouraging antitumor activity and a tolerable safety profile when administered intraperitoneally using TheraPlas technology in patients with ovarian cancer, according to Premal Thaker, MD, MS.

The investigational agent IMNN-001 is an IL-12 DNA plasmid vector encased in a nanoparticle delivery system. Encasement enables cell transfection followed by persistent, local secretion of the IL-12 protein, thus enabling efficacy by recruiting an anti-cancer immune response.^1,2 The agent demonstrated early efficacy in the phase 2 OVATION-2 trial (NCT03393884), and findings presented at the 2024 SITC Annual Meeting showed that patients with newly diagnosed advanced epithelial ovarian cancer who received the agent at a weekly dose of 100 mg/m2 plus chemotherapy (n = 58) achieved a median progression-free survival of 14.9 months vs 11.9 months in the chemotherapy alone arm (n = 54; HR, 0.79; 95% CI, 0.51-1.23).²

“[It’s important] that we’re giving [the drug IMNN-001] in the tumor microenvironment; it’s given intraperitoneally unlike a lot of other drugs which are developed to give be given intravenously. We’re trying to target where the tumor is located,” Thaker said in an interview with OncLive^®. “Additionally, the key is that we’re able to give it repetitively. This molecule is given intraperitoneally on a weekly basis which is a big benefit because sometimes if you have too many adverse effects [AEs], you can’t repetitively dose patients, and here we’re able to successfully do that. We hope that we [can] get better [efficacy] because of the repetitiveness of trying to get the immune system boosted with IL-12.”

In the interview, Thaker discussed considerations when targeting IL-12 in ovarian cancer and how IMNN-001 has shown the potential to do so. She also detailed data with IMNN-001 seen in OVATION 2 in a subsequent article. Thaker is the David G. and Lynn Mutch Distinguished Professor of Obstetrics and Gynecology, director of Gynecological Oncology Clinical Research, and interim chief of the Division of Gynecologic Oncology at Siteman Cancer Center in St Louis, Missouri.

OncLive: How has targeting IL-12 evolved in the past year?

Thaker: In the past year, IL-12 [targeting] hasn’t evolved except for with the technology [from the] OVATION 2 trial which is using an IL-12 gene in a plasmid that is not biodegradable. [Therefore], it’s able to be administered locally, so that you can rechallenge the tumor microenvironment over and over again; that makes this a very novel administration because it’s given intraperitoneally where the cancer is located and [is also] able to be given repetitively, which we have not been able to do previously with other IL-12 molecules that have been developed.

How are investigators seeking to improve upon the efficacy of IL-12–based immunotherapies?

IL-12 has been like the holy grail—everyone has known the importance of it from the 1990s onwards and many companies have tried to develop an IL-12 targeted agent, whether it be a monoclonal antibody [or] other recombinant technologies, without success and a lot of toxicity. There have been approximately over 30 different trials that have been done with prior IL-12 agents, but [they were] not [done] successfully because we haven’t been able to either give the right dose, escalate the dose up, or AEs [were too toxic]. There was a lot of concern [surrounding this because] we know this is a great target, but how are we going to be able to give [IL-12 targeted drugs such as IMNN-001] safely to patients? Now we have that technology [from OVATION 2] which has made it very exciting because we know there’s such a powerful impact of IL-12 in cancer biology.

What is the potential of targeting IL-12 in ovarian cancer in particular?

This platform, [TheraPlas] by IMUNON, is very unique because it has this plasmid TheraPlas technology, which allows us to give the IL-12 gene locally, trying to change that microenvironment of ovarian cancer. Ovarian cancer has always been thought to be a cancer where we have to get the immune system to recognize it. For a very long time, we’ve known that if we can infiltrate the tumor with T cells we are going to be able to get a better response. IL-12 is very important in both your adaptive as well as your innate immune system. We’re trying to change that immunosuppressive tumor biology of ovarian cancer by giving a boost with IL-12.

[IMNN-001] has been the first molecule that’s been able to show that. We’ve been able to show it in patient samples—we create this environment locally in the ascites of patients, as well as in the tumor, but not in the bloodstream. Prior molecules had high doses of IL-12 in the bloodstream, and that’s what caused high fevers [and] many AEs in patients because this big systemic response [was occurring where] you could not get the benefit of it for cancer fighting, but you unfortunately got all of the AEs. Now we’re able to harness IL-12 in this novel mechanism that allows us to get the immune system revved up to try to eradicate cancer.

References

1. IMUNON presents positive data from phase 2 OVATION 2 clinical trial of IMNN-001 in advanced ovarian cancer at SITC 39th Annual Meeting. News Release. IMUNON. November 7, 2024. Accessed November 26, 2024. https://www.globenewswire.com/news-release/2024/11/07/2976849/0/en/IMUNON-Presents-Positive-Data-from-Phase-2-OVATION-2-Clinical-Trial-of-IMNN-001-in-Advanced-Ovarian-Cancer-at-SITC-39th-Annual-Meeting.html
2. Thaker PH, Richardson DL, Hagemann AR, et al. Phase I/II study of safety and efficacy of intraperitoneal IMNN-001 with neoadjuvant chemotherapy of paclitaxel and carboplatin in patients newly diagnosed with advanced epithelial ovarian cancer. Presented at: 2024 SITC Annual Meeting; November 6-10, 2024; Houston, TX. Abstract 1505.