USC scientists engineer self-renewing immune precursor cells that continuously fight cancer in mice

For years, scientists have known that macrophages — the immune system's 'big eaters' — naturally infiltrate tumors and can rally other immune cells to attack cancer. The problem has been turning that knowledge into a treatment: mature macrophages are nearly impossible to grow in large numbers outside the body, difficult to genetically modify, and prone to getting trapped in the lungs and liver rather than reaching a tumor. A team at the University of Southern California may have found a way around every one of those obstacles — by going back to the cell before the macrophage.

In a study published in the journal Cell, USC Stem Cell researchers report that they can grow virtually unlimited quantities of granulocyte-monocyte progenitors (GMPs) — immature immune cells that eventually develop into macrophages and related cell types — in the laboratory, genetically engineer them to recognize and attack cancer, and inject them into mice, where they settle into the bone marrow and continuously generate tumor-fighting immune cells. In mouse models of both blood cancers and solid tumors, the engineered progenitors slowed disease progression more durably than mature macrophage therapies have managed.

The study establishes a scalable and engineerable GMP platform for cellular immunotherapy and introduces concepts that we believe could have broad implications for both cancer immunotherapy and stem cell biology.— Qi-Long Ying, MD, PhD, professor of stem cell biology and regenerative medicine, Keck School of Medicine of USC

The finding also upends a long-held principle in biology. Stem cells are defined in part by their ability to self-renew — to keep dividing while maintaining their identity. Progenitor cells like GMPs, which are further along in development and already committed to producing a narrower range of cell types, were not thought to share that capacity. The USC team showed that under precisely controlled laboratory conditions, GMPs can do exactly that, dividing extensively without maturing prematurely. According to Inside Precision Medicine, the researchers achieved expansion levels approaching eight orders of magnitude while the cells retained their progenitor characteristics.

The prevailing view has been that long-term self-renewal in the blood system is primarily a property of the hematopoietic stem cells that can generate any type of blood or immune cell. We found that, under the right conditions, GMPs can also self-renew, dividing extensively while keeping their identity and ability to produce functional immune cells. That gives us a scalable starting point for engineering cell therapies for cancer, infectious disease and potentially many other conditions.— Qi-Long Ying, MD, PhD

The key was a precisely defined chemical cocktail. According to Science Daily, the mixture prevented the cells from differentiating into mature immune cells prematurely, preserving a renewable population of progenitors that could still develop into functional macrophages and other immune cells when needed. Co-author Daniel McKim, PhD, told Inside Precision Medicine that the self-renewal happens in culture; once transplanted into animals, the GMPs behave like normal progenitor cells, producing downstream immune populations before eventually becoming depleted — but not before establishing a sustained supply from the bone marrow.

This is the first time we can pick single progenitor cells and expand them in large quantities without differentiation. They retain the original identity.— Qi-Long Ying, PhD

With a scalable supply of GMPs in hand, the team then engineered them for cancer combat. They added a chimeric antigen receptor, or CAR — the same basic technology used in CAR-T cell therapy — which allows the cells to recognize a specific marker on cancer cells. They also added a second signal designed to activate nearby immune cells, which in turn stimulate tumor-fighting T cells and amplify the body's broader defenses. Critically, according to EurekaAlert, this added signal works even when the donor cells and the recipient are immunologically mismatched, meaning the therapy could potentially be manufactured in advance from donor cells and given to many patients — an 'off-the-shelf' approach rather than one built individually from each patient's own cells.

When injected into mice, the engineered GMPs did not pool in the lungs and liver the way mature macrophages tend to. Instead, they distributed broadly and engrafted in the bone marrow and other blood-forming niches, where they generated a continuous supply of engineered macrophages and other immune cells. In mice with blood cancer and solid tumors, GMPs carrying only the CAR delayed disease progression; those carrying both the CAR and the immune-activating signal provided an even greater benefit, according to EurekaAlert.

The macrophage angle is particularly significant for solid tumors — cancers that form masses in organs and tissues — where existing CAR-T therapies have struggled. Tumors often create suppressive microenvironments that blunt T-cell activity. Macrophages naturally migrate into those environments and can help reshape them.

Monocytes and macrophages love going into tumors. They can kill tumor cells themselves, but they can also help generate a natural antitumor immune response by the host.— Daniel McKim, PhD, co-author

One of the big issues has been that it's hard to engineer these cells, and when you put them back into the body they don't get where they need to go. The progenitors solve both problems. They're easy to engineer, and they expand after transplantation.— Daniel McKim, PhD

The platform's potential was independently validated. Collaborators in the laboratory of Ravi Majeti, MD, PhD, Director of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University, separately reproduced the long-term maintenance and genetic engineering of GMPs, according to EurekaAlert.

This method for the expansion and engineering of GMPs opens the door to numerous translational applications, much like T cell expansion and engineering. We have already demonstrated engineering of these cells to drive multiple potent functions, and there is a lot more to be explored.— Ravi Majeti, MD, PhD, Stanford University

The researchers also demonstrated applications beyond cancer. In mice with chronic granulomatous disease — an inherited immune deficiency — the GMPs restored the ability to fight bacterial infection, according to EurekaAlert.

The work remains preclinical; all experiments were conducted in mice, and human clinical trials have not yet begun. But the researchers believe the platform reframes a fundamental question in immunotherapy design.

Our study suggests that the future of immunotherapy may depend not only on designing better CAR receptors, but also on choosing the right developmental stage of the cell.— Qi-Long Ying, MD, PhD

Why it matters — If the approach translates to humans, it could provide a scalable, potentially off-the-shelf source of genetically armed immune cells capable of reaching and attacking solid tumors — the category of cancer where existing immunotherapies have had the least success.

Reported by sciencedaily.com, eurekalert.org, sciencealert.com, insideprecisionmedicine.com