The advent of checkpoint inhibitors yielded a big win for the burgeoning immuno-oncology space, supercharging activated T cells to attack cancer cells, and the success with drugs targeting CTLA-4 and PD-1 has translated into efforts chasing other checkpoint mechanisms, all in the hopes of expanding the stunning results into broader patient populations.
But it also raised the question of how to get those T cells going in the first place. "Targeting the tumor microenvironment is the next step to answering that question," said Steve James, executive chairman and interim CEO of 2015 startup Pionyr Therapeutics Inc.
Pionyr was co-founded by Max Krummel, a professor at University of California, San Francisco School of Medicine, and Sachdev Sidhu, a former Genentech scientist and now head of protein engineering and antibody discovery at the University of Toronto. Krummel, in particular, already had an impressive reputation in the immuno-oncology, or I-O, field, having been one of the patent-holders for CTLA-4-targeting antibody Yervoy (Bristol-Myers Squibb Co.), the first checkpoint inhibitor to clear regulatory hurdles.
"When I heard he was working on a new hypothesis, I thought it sounded very interesting," said James, who already had "become enamored by the immuno-oncology space."
James, whose prior positions include CEO of Labrys Biologics Inc. (acquired by Teva Pharmaceutical Co. Ltd.) and Kai Pharmaceuticals Inc. (acquired by Amgen Inc.), came on board with a group of angel investors in the summer of 2015. At the time, the company was known as Precision Immune, a name that accurately embodied the company's goal but lacked a little punch, prompting the founders to devise a name that evoked the "pioneering" work of the startup.
Pionyr raised $8 million in mid-2016, "and that has really fueled the company into the early part of 2018, and allowed us to start to hire people," James said.
A key hire was Michel Streuli, whose CV includes heading I-O efforts at Gilead Sciences Inc. and at Merck & Co. Inc., where he worked on what would become anti-PD-1 antibody Keytruda (pembrolizumab), a drug that hit blockbuster status in 2016 with sales of $1.4 billion.
"It's been known for a long time that tumors have T cells and macrophages that have co-evolved with the tumor and allow, if not promote, tumor growth," Streuli said. But rather than boosting the activity of activated T cells, Pionyr's approach aims at altering – or tuning – the tumor microenvironment so that immune-activating cells are favored over immune-suppressing cells.
The technology, called Myeloid Tuning, is designed to adjust the cellular infiltrate of the tumor microenvironment. Krummel "was able to show that certain types of myeloid cells can promote or actively inhibit cells," Streuli said. Krummel helped develop a subset of different subpopulations of dendritic cells, largely defined by their surface antigens, zeroing in on antigens that are transmembrane proteins.
"So you really have three options," Streuli explained, including using an antibody to activate a cell if a dendritic antigen is presenting or revving up the antigen presentation on positive cells.
"Right now, [Pionyr's] main focus is going after the sort of bad myeloid cells and trying to eliminate those cells through an effector mechanism," Streuli said. By tagging those cells with an antigen and delivering an antibody capability of cellular phagocytosis, "we could essentially remove those cells" so the tumor infiltrate carries less tumor-promoting cells.
"We suspect that alone may not be enough," he told BioWorld Today. "You may still need to take off the brakes." So Pionyr already is planning to combine its approach with checkpoint inhibitors.
"The first wave was checkpoint/checkpoint [combination], and a lot of companies are pursuing that," Streuli told BioWorld Today. "But it comes with toxicity. The next frontier is how to become more efficacious without becoming more toxic."
Simply revving up the immune system can result in negative consequences, he added. "We're trying to find orthogonal approaches to balance rather than overactivate" the immune system. "It's early days, but the first set of data we are quite pleased with," he said.
Pionyr hasn't yet disclosed specific indications or development plan. More preclinical work is the current aim. "We're really setting the stage to develop clinical reagents," James said.
The goal is to choose targets that "take us into tumor types that have the highest unmet need, where we can make the biggest impact," he added.
Pionyr also plans to stick with the "tried and true strategy of a company with a platform," creating a portfolio of antibody candidates, and then "pick and choose the ones we would like to partner and pick the ones we can take forward into the clinical ourselves," James told BioWorld Today.
"What I like about immuno-oncology is that you can do substantial big pharma deals earlier than [in] other areas," he said. "You see a lot of deals getting done at a much earlier stage" with the innovator companies retaining more rights.
Going forward, James predicted that "we'll be in money-raising mode before the end of 2017."
Altogether, Pionyr has brought in nearly $10 million since inception. Its latest investment was led by Orbimed and SV Life Sciences and also included Osage University Partners, Mission Bay Ventures and the company's private angel investors.
The company's board includes James and Krummel, along with Michael Ross and Joshua Resnick, both of SV Life Sciences, and Leon Chen, of Orbimed.