Turning the table on CD47, Penn team primes macrophages to ignore 'don't eat me' signal
The growing group of biotechs pursuing the CD47 “don’t eat me” pathway has largely focused on disrupting how the immunosuppressant lulls macrophages into sleep, thereby helping cancer skirt the immune system. But a team of scientists at the University of Pennsylvania now wants to focus on the other side of the interaction, arming macrophages to do the hit job they’d been kept from doing.
By rewiring the metabolism of macrophages — a type of immune cells capable of engulfing cancer cells — one can override the “don’t eat me” signal and unleash an immune attack, the researchers reported in a Nature Immunology paper published on Monday.
While this approach alone was enough to induce rapid shrinkage of tumors and prolonged survival in mice — even when there’s a large presence of CD47 — the big idea here is to set up a one-two punch where geared up macrophages would be ready to eat cancer cells while CD47 inhibitors simultaneously take down the barriers they need to overcome.
“It turns out macrophages need to be primed before they can go to work, which explains why solid tumors may resist treatment with CD47 inhibitors alone,” said Gregory Beatty, senior author of the study and an assistant professor at Penn’s Perelman School of Medicine.
CpG, a toll-like receptor agonist, was used to activate the macrophages.
The researchers — led by Jason Liu, a graduate student in Beatty’s lab — observed that the activated macrophages “began to utilize both glutamine and glucose as fuel to support the energy requirements needed for them to eat cancer cells.”
Their publication comes amid early snapshots of data from CD47 blockade programs that show varying degrees of success. Surface Oncology was forced to rein back trials of its lead antibody after tracking low-dose toxicity in a Phase I study while Forty Seven is forging ahead with promising Phase Ib results. The field — which has long attracted academic interest — also features other contenders like Boehringer Ingelheim and Arch Oncology (formerly Tioma Therapeutics), which is backed by Roche, and RiverVest and 3×5 Partners.