By using engineered retinal pigment epithelial cells to deliver IL-2 into the tumor microenvironment, investigators at Rice University eradicated ovarian and colorectal tumors in mouse models, and elicited T-cell responses after implantation in primates.

The team published its findings in the March 2, 2022, issue of Science Advances.

Cytokines are critical to activating the immune system against tumors and infections. IL-2, which is normally produced primarily by activated CD4 T cells, affects both T cells and natural killer (NK) cells. Recombinant IL-2 is approved for the treatment of renal cell carcinoma and metastatic melanoma, and NK-cell therapies in clinical development are often administered in combination with recombinant IL-2 as well.

However, IL-2, as well as other cytokines, are toxic at high doses – and the current delivery methods need high doses to be effective.

Cytokines are typically delivered intravenously, which means that before they make it into tumors, they travel through the blood, which is itself full of immune cells.

The situation is exacerbated by natural IL-2's instability. In the blood, the cytokine degrades in a matter of minutes.

Between the concentration gradient, with more cytokines in the blood, and the presence of immune cells, Amanda Nash told BioWorld, "patients often get off target side effects and very little cytokine actually makes it to the tumor site."

Nash is the paper's first author, and a graduate student in senior author Omid Veiseh's lab at Rice University.

Researchers are testing multiple modifications to improve IL-2 functionality, including increasing its stability, modifying its affinity for different receptors, and conjugating it to antibodies. But to date, the Rice investigators argued in their paper, "an approach to simultaneously account for the short lifetime, maintain the full biological activity, and limit systemic toxicity of IL-2 remains elusive."

The method uses engineered retinal pigment epithelial (RPEs) cells to produce IL-2 in vivo. RPE cells are a major part of the retina, supporting photoreceptors in their function. RPE cells were some of the earliest cell types to be used in gene and cell therapy. Starting in 2007, one experimental option for Leber congenital amaurosis, a rare cause of blindness, is gene therapy to replace RPE-65.

And in 2015, RPE cells became the world's first of iPS-derived cells to be transplanted, when clinicians at Kobe City Medical Center General Hospital used them to treat a patient with age-related macular degeneration.

But the cell type has a second line of work outside of the eye.

Veiseh, who is an assistant professor of bioengineering at Rice University, told BioWorld that RPE cells "have been tested in clinical trials in the context of drug delivery for decades and other companies have used these cells in the past and have been shown to be potent producers of biologics."

The team chose RPE cells for their work, he said, because "we wanted to leverage cells that have been previously used in clinical trials and can be genetically manipulated."

Nash, Veiseh and their colleagues encapsulated the cells to avoid immune attack, and implanted them into the peritoneal cavity of mice with metastatic ovarian cancer. The approach, Nash said, enabled "high cytokine concentrations at the tumor site without disrupting the immune cells in the blood." They "can be implanted in various cavities, subcutaneously, or even intratumorally to evoke an immune response where needed."

"Initially we were trying to develop ways to continuously deliver cytokines systemically. But we discovered that this concentration gradient existed and that we could leverage this gradient to deliver high local concentrations of cytokines while limiting systemic exposures."

In the work now published in Science Advances, the team showed that treating mice with the IL-2 producing RPE cells was more effective at reducing tumor burden than treatment with injected IL-2, and RPE-treated mice survived significantly longer.

In a mouse model of colorectal cancer, treatment with the engineered RPE cells both reduced tumor burden and protected mice from recurrence, suggesting that treatment spurred the development of memory T cells.

In a set of experiments with cynomolgus monkeys, the investigators demonstrated that implantation spurred the development of CD "killer" T cells, but not of immune suppressive regulatory T cells, but did not cause the toxicities that have hampered IL-2 treatments in the clinic.

Veiseh is also a co-founder of and advisor to Avenge Bio, which has licensed the technology, called Lococyte, from Rice University. Founded in 2019, the company closed a USD 45 million Series A round in January this year. Veiseh said that the company is "moving forward to human clinical trials in late 2022."

In a press release, Avenge Bio called the paper "foundational, preclinical research establishing the Lococyte platform proof of concept in animal models."

Vesieh said his own team is "also planning to test this system in other cancer models, such as lung cancer, where we would administer the capsules in the pleural cavity."