Scientists from Rice University and the Baylor College of Medicine report that they can eradicate advanced-stage mesothelioma tumors in mice in only a few days with a treatment combining Rice’s cytokine “drug factory” implants and a checkpoint inhibitor drug. The team administered the drug-producing beads, which are about the size of the head of a pin, next to tumors where they could produce continuous, high doses of interleukin-2 (IL-2), a natural compound that activates white blood cells to fight cancer.

The study “Activation of adaptive and innate immune cells via localized Interleukin-2 cytokine factories eradicates mesothelioma tumors,” published online in Clinical Cancer Research, describes the drug-factory technology invented in the lab of Rice bioengineer Omid Veiseh, PhD. The FDA have given its approval to begin clinical trials of the technology this fall in ovarian cancer patients.

“Interleukin-2 (IL-2) immunotherapy has the potential to elicit immune-mediated tumor lysis via activation of effector immune cells, but clinical utility is limited due to pharmacokinetic challenges as well as vascular leak syndrome and other life-threatening toxicities experienced by patients. We developed a safe and clinically translatable localized IL-2 delivery system to boost the potency of therapy while minimizing systemic cytokine exposure,” write the investigators.

From left: Amanda Nash, Omid Veiseh, and Samira Aghlara-Fotovat [Jeff Fitlow/Rice University]

“We evaluated the therapeutic efficacy of IL-2 cytokine factories in a mouse model of malignant mesothelioma. Changes in immune populations were analyzed using time-of-flight mass cytometry (CyTOF), and the safety and translatability of the platform were evaluated using complete blood counts and serum chemistry analysis.

“IL-2 cytokine factories enabled 150x higher IL-2 concentrations in the local compartment with limited leakage into the systemic circulation. AB1 tumor burden was reduced by 80% after one week of monotherapy treatment, and 7/7 of animals exhibited tumor eradication without recurrence when IL-2 cytokine factories were combined with aPD1. Further, CyTOF analysis showed an increase in CD69+CD44+ and CCD69-CD44+CD62L+ T cells, reduction of CD86-PD-L1- M2-like macrophages, and a corresponding increase in CD86+PD-L1+ M1-like macrophages and MHC II+ dendritic cells after treatment. Finally, blood chemistry ranges in rodents demonstrated the safety of cytokine factory treatment and reinforced its potential for clinical use.

“IL-2 cytokine factories led to the eradication of aggressive mouse MM tumors, protection from tumor recurrence, and increased the therapeutic efficacy of anti-PD1 checkpoint therapy. This study provides support for the clinical evaluation of this IL-2-based delivery system.”

“From the beginning, our objective was to develop a platform therapy that can be used for multiple different types of immune system disorders or different types of cancers,” said Rice graduate student Amanda Nash, who spent several years developing the implant technology with study co-lead author Samira Aghlara-Fotovat, a fellow student in Veiseh’s lab.

The cytokine factories consist of alginate beads loaded with tens of thousands of cells that are genetically engineered to produce natural IL-2, one of two cytokines the FDA has approved for treatment of cancer. The factories are 1.5 millimeters wide and can be implanted with minimally invasive surgery to deliver high doses of IL-2 directly to tumors, according to the researchers.

In the mesothelioma study, the beads were placed beside tumors and inside the thin layer of tissue known as the pleura, which covers the lungs and lines the interior wall of the chest.

“I take care of patients who have malignant pleural mesothelioma,” said Bryan Burt, MD, professor and chief of Baylor’s Division of Thoracic Surgery in the Michael E. DeBakey Department of Surgery. “This is an aggressive malignancy of the lining of the lungs. And it’s hard to treat completely by surgical resection. In other words, there is often residual disease that is left behind. The treatment of this residual disease with local immunotherapy—the local delivery of relatively high doses of immunotherapy to that pleural space—is an attractive way to treat this disease.”

Early ovarian cancer animal test results

Veiseh said the mesothelioma study began when Burt and Baylor surgeon and associate professor Ravi Ghanta, MD, heard about the early results of ovarian cancer animal tests Veiseh’s team was conducting with collaborators at the University of Texas MD Anderson Cancer Center. In March, Veiseh and MD Anderson collaborators published a study showing IL-2-producing beads could eradicate advanced-stage ovarian and colorectal tumors in mice in less than a week.

“They were really impressed by the preclinical data we had in ovarian cancer,” Veiseh said of Burt and Ghanta. “And they asked the question, ‘Could we actually leverage the same system for mesothelioma?’”

Mesothelioma refers to any cancer that occurs in the tissue linings that surround and protect internal organs. About 80% of mesothelioma cases are linked to prolonged exposure to asbestos.

In the mesothelioma study, the Rice-Baylor team tested Veiseh’s drug factory implants both by themselves and in combination with a checkpoint inhibitor that targeted the PD-1 protein. They found the drug factory implants eliminated tumors in more than 50% of the treated animals when used by themselves. Tumors were destroyed completely in all seven mice that were treated with both the drug factory implants and PD-1 checkpoint inhibitor.

“It’s hard to treat mesothelioma tumors in mice, like it is in human beings,” said Burt, who also is a member of the Dan L. Duncan Comprehensive Cancer Center at Baylor. “And what our data show is that delivery of these immunotherapy particles, regionally, to these mice who have mesothelioma, has provocative and effective treatment responses. In fact, I’ve not seen these mesothelioma tumors in mice be eradicated, with such efficacy, as we have in this mouse model.”

Veiseh said the results also suggested that the combination of IL-2-producing implants and anti-PD-1 checkpoint inhibitors could be effective at training “memory T cells” that can reactivate the immune system to fight mesothelioma if it recurs.

“We have a spinout company, Avenge Bio, that recently received clearance from the FDA to treat ovarian cancer patients, and in the next couple of months they expect to begin treating patients with these IL-2 cytokine factories,” explained Veiseh.

“The preclinical data reported in our latest manuscript helped justify initiating a second clinical trial for patients suffering from mesothelioma and other lung cancers with pleural metastasis. We have held meetings with the FDA and expect to initiate a second trial for this patient population in the latter half of 2023.”

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