Last week, Threshold Pharmaceuticals Inc. announced the failure of two phase III evofosfamide trials, one in pancreatic cancer and another in soft tissue sarcoma, but Barry Selick, CEO of the South San Francisco-based company, gave investors some hope that the drug might work in combination with immune checkpoint inhibitors. (See BioWorld Today, Dec. 8, 2015.)

"If we had all the data today that we had four years ago, are pancreatic and sarcoma the two indications that we would have gone after at that time?" Selick asked during a conference call going over the data and future plans for evofosfamide (previously designated TH-302). "I suspect that the answer is probably no in light of what we've seen working with Michael Curran and his group at MD Anderson combining 302 with checkpoint inhibitors."

At the Society for Immunotherapy of Cancer (SITC) annual meeting last month, Curran's laboratory presented data showing that hypoxic zones in prostate tumors resist infiltration by T cells. Evofosfamide is designed to be activated under hypoxic conditions, which opened up the hypoxic zones to T-cell infiltration. Evofosfamide thereby helped sensitize tumors to anti-CTLA-4/anti-PD-1 treatment in animal models.

ENHANCING ACTIVITY

Threshold isn't the only company taking that approach; many biotechs have announced plans to test combinations of their therapies with immuno-oncology therapies.

"Sometimes you'll see groups that seem like they're randomly testing combinations," Thomas Dubensky Jr., chief scientific officer at Aduro Biotech Inc., told BioWorld Insight.

Berkeley, Calif.-based Aduro is taking a more rational approach, giving new life to the prostate cancer vaccine GVAX, which has a checkered past having been tested by Cell Genesys Inc., which merged with Biosante Pharmaceuticals Inc., before being purchased by Aduro.

While GVAX's overall response rate wasn't that great, patients who responded had CD8+ T cells in their tumors, suggesting that up-regulating the immune system could enhance GVAX's activity.

Aduro's CRS-207 is a live-attenuated listeria that secretes mesothelin into the cytosol of antigen presentation cells (APCs) that take up the listeria. The APCs go on to activate T cells to attack the tumor.

The company is testing the combination in pancreatic cancer in a phase IIb trial, dubbed ECLIPSE, which is scheduled to read out in the first half of next year.

A second phase IIb trial, STELLAR, adding checkpoint inhibitor Opdivo (nivolumab, Bristol-Myers Squibb Co.) to GVAX and CRS-207 should produce results in the second half of next year. Dubensky noted that Opdivo and the other PD-1 checkpoint inhibitors haven't had much success as monotherapies to treat pancreatic cancer.

"We're answering the question if one plus one equals three," Dubensky said.

MULTIPLE CHECKPOINTS

Likewise, Peregrine Pharmaceuticals Inc. said it makes sense to test its drug, bavituximab, with a drug targeting the PD-1 pathway. Bavituximab targets phosphatidylserine, a molecule released during apoptosis that down-regulates the immune cells to keep the immune system from mounting a major response against a few cells that have died.

"Tumors hijack this pathway," Steven King, president and CEO of Tustin, Calif.-based Peregrine told BioWorld Insight. Tumors can outgrow their blood supply causing cells to die, but phosphatidylserine acts as a checkpoint, dampening the immune response against a tumor.

Peregrine is currently testing bavituximab with docetaxel compared to docetaxel alone in SUNRISE, a phase III trial in previously treated non-small-cell lung cancer patients that is scheduled to read out next year.

Earlier this year, Peregrine partnered up with Astrazeneca plc to test the pharma's anti-PD-L1 immune checkpoint inhibitor, durvalumab, with bavituximab, after preclinical data suggested that the combination might help even if tumors don't initially express PD-L1. By removing the phosphatidylserine checkpoint, the immune system is activated, but the tumor can then use PD-L1 to inhibit the immune system.

Durvalumab should help perpetuate the bavituximab-induced immune response, while boosting the opportunity for durvalumab in tumors that are not expressing PD-L1 until the bavituximab treatment. "It's sort of a win-win situation," King said.

King said he thinks that bavituximab will likely work with any of the drugs targeting the PD-1 pathway, but decided to work with London-based Astrazeneca rather than one of the FDA-approved drugs, in part, because Astrazeneca was willing to provide the drug free of charge.

"We save probably as much as we're spending because of the cost of these drugs," King said.

CHANGING COURSE

Heat Biologics Inc. was so convinced that its drug would work better in combination with an immune system checkpoint inhibitor that it stopped enrolling a lung cancer phase II trial midstream to test its injectable adenocarcinoma cell vaccine, HS-110 (viagenpumatucel-L), in combination with Opdivo. (See BioWorld Today, Sept. 2, 2015.)

The Durham, N.C.-based company cited the change in the standard of care for lung cancer patients as the reason for stopping the phase II trial and starting a new phase Ib trial testing HS-110 and Opdivo. Top-line data from the new 18-patient trial are expected in the fourth quarter of 2016.

HS-110 is made from modified lung cancer cells designed to stimulate the immune system to attack the tumor. Like Peregrine's bavituximab, the idea is that HS-110 can stimulate the immune system, potentially helping Opdivo work on patients that the checkpoint wouldn't normally be able to help.

WE LIKE YOU A LOT

While New York-based Bristol-Myers Squibb (BMS), Astrazeneca and other companies with immune system checkpoint inhibitors have been willing to provide free drugs and other financial support for biotechs to test their drugs in combinations, Bavarian Nordic A/S got a major endorsement from BMS when the pharma licensed Bavarian Nordic's Prostvac. BMS paid $60 million up front and offered an innovative milestone payment plan based on the length of overall survival that Prostvac produces in the ongoing phase III trial. (See BioWorld Today, March 5, 2015.)

"We believe the terms are favorable, but importantly the BMS deal also provides some third-party validation on the wealth of phase I-II data, phase III plan, and technology platform, as well as facilitating the expedited initiation of further clinical trials including in combination with checkpoint inhibitors." Jefferies International Ltd. analyst Peter Welford wrote in a note to clients at the time.

Not surprisingly, Bavarian Nordic recently announced plans to start a phase II combination study of Prostvac and BMS' other immuno-oncology therapy, Yervoy (ipilimumab), in collaboration with BMS and a second phase II triple-combination study with Prostvac, Yervoy and Opdivo in collaboration with the National Cancer Institute.

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