Researchers from Rice University and the Baylor School of Drugs have shown they can eradicate advanced-stage mesothelioma tumors in mice in just a few days through a treatment combining Rice’s cytokine “drug factory” implants and a checkpoint inhibitor drug.
Researchers delivered the drug-producing beads, which are no bigger than a pinhead, next to tumors where they could produce continuous high doses of interleukin-2 (IL-2), a natural compound which energizes white blood cells to fight cancer.
The study, published online today in Scientific Most cancers Research, is the latest in a series of successes for the drug factory technology invented in the lab of bioengineer Rice Omid Veiseh, including Food and Drug Administration approval to begin clinical trials of the technology this fall in patients with most ovarian cancers.
“From the beginning, our goal was to develop a platform therapeutic that can be used for many kinds of immune system problems or different kinds of cancers,” said Rice graduate student Amanda Nash, who spent several years developing the implant technology with the study co-author. Principal Samira Aghlara-Fotovat, a student in Veiseh’s lab.
Cytokine factories are made of alginate beads loaded with tens of thousands of cells genetically engineered to produce ‘Natural IL-2, one of two cytokines approved by the FDA for the treatment of most cancers. The plants are just 1.5 millimeters wide and can be implanted with minimally invasive surgery to deliver high doses of IL-2 directly to tumors. In the mesothelioma study, the beads were placed next to tumors and inside the thin layer of tissue known as the pleura, which covers the lungs and lines the inside wall of the chest.
“I care for patients with malignant pleural mesothelioma,” said Dr. Bryan Burt, professor and head of Baylor’s division of thoracic surgery in the Michael E. DeBakey. “This is a very aggressive malignant tumor of the lining of the lungs. And it is very difficult to treat it completely by surgical resection. In other words, there is often residual disease left. Treating this residual disease with local immunotherapy — local delivery of relatively high doses of immunotherapy to this pleural space — is a very attractive way to treat this disease.
Veiseh a said the mesothelioma study began when Burt and Baylor surgeon and associate professor Dr. Ravi Ghanta heard about the initial results of the ovarian cancer animal tests that Veiseh’s team was conducting with collaborators from the University of Texas MD Anderson Most Cancers Heart. In March, Veiseh collaborators and MD Anderson published a study showing that IL-2-producing beads could eradicate advanced-stage ovarian and colorectal tumors in mice in less than a week.
“They were really impressed with the preclinical data we had on ovarian cancer,” said Veiseh said of Burt and Ghanta. “And they asked the question, ‘Could we actually use the same system for mesothelioma?’”
Mesothelioma refers to any cancer that occurs in the tissues that surround and protect the internal organs. Approximately 80% of mesothelioma cases are linked to prolonged exposure to asbestos.
Immunotherapy with drugs called checkpoint inhibitors has met with particular success in the treatment of mesothelioma. Checkpoint inhibitors do not kill cancer directly, but rather by training the immune system to recognize and destroy cancer cells.
In the mesothelioma study, the Rice-Baylor team tested Veiseh’s drug factory implants alone and in combination with a control level inhibitor targeting the PD-1 protein. They found that the drug plant implants eliminated tumors in more than % of treated animals when used alone. Tumors were completely destroyed in the seven mice that were treated with both the drug plant implants and the control position inhibitor PD-1.
“It’s very difficult to treat mesothelioma tumors in mice, as it is in humans,” said Burt, who is also a member of the Dan L. Duncan Complete Cancer Heart at Baylor. “And what our data shows is that administering these immunotherapy particles, regionally, to these mice with mesothelioma, has very provocative and very effective therapeutic responses. In fact, I have not seen these mesothelioma tumors in mice eradicated, with such efficiency, as we have in this mouse model.
Veiseh said the results also suggest that the combination of IL-2-producing implants and anti-PD checkpoint inhibitors -1 could be effective in creating “memory T cells” that can reactivate the immune system to fight mesothelioma if it recurs.
“We have a spin-off company, Avenge Bio, which recently received FDA clearance to treat patients with most ovarian cancers, and within the next two months they plan to begin treating patients with these IL-2 cytokine factories. ”, said Veiseh.
“The preclinical data reported in our latest manuscript helped to justify the launch of a second clinical trial for people suffering from mesothelioma. and other lung cancers with pleural metastases,” Veiseh said. “We have held meetings with the Food and drug administration and expect to initiate a second trial for this patient population in the second half of 80.”
In addition to cancer research, Veiseh and Ghanta received a grant from the American Heart Association to study the potential of cytokine implants for healing heart damage caused by seizures
The research was funded by the Most cancers Prevention Exploration Institute of Texas (RR160047), the Countrywide Science Foundation (1842494) and the National Institutes of Health and Fitness (R01DK120459-01).