IL-12 TO RESCUE IN CANCER?
Body electric: Oncosec sings praise of booster bid for immunotherapy
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By Randy Osborne
Staff Writer
Monday, December 1, 2014
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The approval this fall of Merck & Co. Inc.'s lauded Keytruda (pembrolizumab) for melanoma – well ahead of its Oct. 28 PDUFA date – opened the door for the promising class of programmed cell death-1 (PD-1) inhibitors, and represented another stride in the steady march of immunotherapy in cancer.
Whitehouse Station, N.J.-based Merck was the first to file a biologics license application for a drug targeting PD-1, ahead of closest competitor nivolumab, from Bristol-Myers Squibb Co. (BMS), of New York, though BMS' drug was the first to win approval in Japan, where it is branded Opdivo and partnered with Osaka, Japan-based Ono Pharmaceutical Co. Ltd. (See BioWorld Today, May 7, 2014, July 9, 2014, and Sept. 5, 2014.)
Some estimates peg sales of cancer immunotherapies as high as $30 billion by 2025, and more than half of cancer therapies are expected to have immunotherapy as their backbone within the next decade.
Keytruda was cleared for use in patients with advanced or unresectable melanoma who are no longer responding to other drugs. But as much as 70 percent of patients do not respond to the drug, and finding a way to change this – for Keytruda and other immunotherapies – could mean big money.
Enter Oncosec Medical Inc., of San Diego, with its drug/device electroporation approach, Immunopulse pIL-12, by way of which DNA interleukin-12 (IL-12) – a plasmid DNA construct with "instructions" to produce the IL-12 protein – is delivered into the electroporated cells. The gene then triggers each cell to produce and secrete the IL-12 protein, which goes after cancer cells as part of natural immune response.
"Even though melanoma is a very tractable tumor type," said Punit Dhillon, CEO of Oncosec, tumor-infiltrating lymphocytes (TILs) are in short supply with the disease, and the "low-TIL environment" keeps PD-1 drugs such as Keytruda from working in more patients. "What we can do with Immunopulse, specifically because we're using IL-12, is bring the immune cells to that environment," he told BioWorld Today.
Oncosec this month entered a collaboration with the University of California, San Francisco (UCSF), to evaluate the safety, tolerability and efficacy of the combination of Keytruda and Immunopulse in melanoma. Enrollment is expected to begin in the first quarter of next year. Also this month, the firm kicked off a preclinical collaboration with Plexxikon Inc., part of Daiichi Sankyo Co. Ltd., of Tokyo, to test the combination of Plexxikon's selective colony-stimulating factor-1 receptor (CSF1R) inhibitor with Immunopulse pIL-12. Recent interim data from Oncosec's phase II study in melanoma showed that local delivery of IL-12 by electroporation increases the production of cytokines like IFN-?, resulting in increased expression of genes related to the processes required for cytotoxic CD8-positive T cells to recognize and kill cancer cells, the company noted.
"There are a lot of different choices out there for delivery – such as viruses, lipids or other biologic means," Dhillon said, but electroporation has the benefit of being "very clean, with no side effects or lingering issues left over." Oncosec, he said, is "the only company doing it intratumorally and the first company delivering gene therapy using in vivo electroporation," though other firms are advancing in somewhat similar areas. Dhillon cited as an example Inovio Pharmaceuticals Inc., of Plymouth Meeting, Pa., which delivers into muscle. "We believe it's important to bring the fight to the tumor and have the specific antigen response in the tumor micro-environment," he said.
Dhillon was the vice president of finance and operations at Inovio. "We were the pioneers in the electroporation space," he said, adding that the intellectual property "was divided up into different tissue types, basically. We didn't have the bandwidth to focus on intratumoral delivery." Spinout Oncosec has "advanced significantly, looking at a whole range of other immune targets and electroporation parameters," he said. (See BioWorld Today, Aug. 12, 2011.)
The firm has several phase II trials enrolling already, with OMS-I100 in metastatic melanoma being conducted in collaboration with UCSF. The open-label, multicenter, phase II trial will enroll about 25 patients with advanced-stage, cutaneous, in-transit malignant melanoma. Trials are under way at three centers across the U.S. Previous data from a phase I study demonstrated that using Immunopulse in melanoma patients is safe and well tolerated, with objective responses (as defined by RECIST criteria) observed in 53 percent of patients.
OMS-I110 targets the rare but deadly Merkel cell carcinoma, with a mortality rate of 40 percent. Because 80 percent of cases are caused by an associated viral infection (Merkel cell polyomavirus), researchers believe an efficient and targeted immunotherapy could be the best hope. Oncosec's safety and efficacy trial is being conducted with the University of Washington. The open-label, multicenter experiment will enroll about 15 patients at two U.S. centers.
In cutaneous T-cell lymphoma, Oncosec has OMS-I120. The phase II study in early and late-stage patients, like the melanoma trials, is being conducted with UCSF. The open-label trial will enroll about 27 patients at a single center.
"Melanoma represents a low-hanging opportunity for us" given the "awesome" data in phase I and phase II trials, Dhillon said. "The monotherapy results speak for themselves. It's pretty unbelievable to see the response in untreated lesions."
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