One of the hottest areas of cancer research involves a protein on cancer cells that shields them from the immune system. Blocking this protein, CD47, is like ringing the dinner bell for macrophages, the immune cells that engulf pathogens.Science of blocking CD47 as a way to get the immune system to target cancer cells has led to 47 biotech companies Gilead Sciences later bought for billions.
Physician/scientist Amira Barkal observed the development of 47 while she was working on her Ph.D.Research in the lab of Stanford University stem cell biologist Irving Weissman, who led to the creation of the biotech company and others. Barkal was not involved in Forty Seven, but she studied CD47 because it is associated with other proteins that signal “don’t eat me” to macrophages. Barkal’s work in Weissman’s lab led to the discovery of a promising new protein, CD24, with potential applications in breast and ovarian cancer. Now she’s the founder of her own biotech startup, Pheast Therapeutics, based in Palo Alto, California.
“Irv embodies the idea that in order for clinical discoveries to be made available to patients, relevant scientists must be involved in clinical development,” Barkal said. “That’s what we do at Pheast.”
Pheast has launched a $76 million in Series A funding $1 million more than original on Tuesday 47 Raised money when it spun out of Stanford in 2016At the time, scientists well understood that targeting 47 could be applied to blood cancers, Barkal said. One of her research goals in Weissman’s lab was to find ways to apply the same approach to solid tumors. For solid tumors, blocking 47 resulted in greater variability in macrophage recognition of cancer, Barkal said. This variability suggests that cancer cells are using another barrier — a different don’t eat me signal.
Dr. Barkal’s title thesis is “Increasing the appetite of macrophages for cancer immunotherapy.” Scientists now know, what they didn’t know at the 47-year-old’s origin, that there are multiple don’t eat me signals in tumors, Barkal said.She is the lead author of a paper post The study was explained in the journal Nature in 2019. According to the paper, the greatest expression of CD24 was observed in ovarian cancer cells. The scientists also found that this protein is abundant in triple-negative breast cancer cells. Blocking 24 on breast and ovarian cancer cells resulted in increased macrophage feeding.
There’s a reason Barkal didn’t name her company Twenty Four. Although the 24 protein is highly expressed in breast and ovarian cancers, it may have mixed roles in other tumor types. In some cases, appropriate treatment may involve blocking47 and 24. In other types, the best approach may be to use a completely different cancer protein. To exploit these signals in immunotherapy, it is critical to understand which signals are present in any given tumor. Pheast’s technology is a platform that classifies “don’t eat me” signals to find the dominant one (or two). There’s no need to block all “don’t eat me” signals, Barkal said. Blocking dominant or codominant signaling should be sufficient to stimulate appetite in macrophages.
“Our goal is to eliminate the ‘don’t eat me’ input for a balanced diet. We don’t need to cover 100 percent,” the don’t eat me signal, she said. “We need to cover the majority.”
Future combinations could include pairings with other types of cancer drugs, possibly including a different blocking therapy called a checkpoint inhibitor, a class of drugs that includes Merck & Co’s Keytruda and Bristol-Myers Squibb’s Opdivo. These drugs block checkpoint proteins that prevent T cells from recognizing tumors. Ovarian and triple-negative breast cancers have historically been less responsive to T-cell immunotherapy, Barkal said. This suggests that another approach, such as recruiting macrophages, could provide a better way to address these hard-to-treat tumors.
Forty-seven of the CD47-blocking drugs are antibodies. Antibodies were used in 24 targeted studies published in Nature, but Barkal said Pheast’s therapy could go in a number of ways. However, one of the problems with antibody drugs targeting 47 is that the protein is also present on red blood cells, meaning that blocking it also makes it recognized by macrophages. In the Nature paper, the scientists wrote that a 24-position blocking antibody had no detectable binding to red blood cells. But the paper also points to a different potential off-target effect. CD24 is abundant in B cells, so targeting the protein with drugs could deplete these immune cells.
Pheast bears the imprint of its ancestors. The startup currently has a team of less than 20 people, including 47 or veterans of the Weissman lab. Barkal said her startup’s expansion includes finding her successor. Barkal, the current interim CEO, said she plans to remain involved with Pheast as lead founder. Pheast’s goal is to bring CD24-targeted therapies into clinical trials, Barkal said, but she declined to provide a timeline. The financing will allow the startup to expand the scope of its technology to uncover more “don’t eat me” signals associated with more cancer types, she added.
“It’s really a long-term vision,” Barkal said. “A global quest for the don’t eat my cancer signal.”
Public domain image from the National Cancer Institute
