Scientists at the University of Southern California (USC) have developed a new cell-engineering platform that could help overcome one of the biggest challenges in cancer immunotherapy: producing sufficient quantities of immune cells for treatment. The approach uses expandable immune progenitor cells that can be genetically engineered and potentially manufactured as off-the-shelf therapies.
The research focuses on granulocyte-monocyte progenitors (GMPs), precursor cells that give rise to macrophages and other immune cells. Macrophages have attracted growing interest in oncology because of their natural ability to infiltrate tumors, engulf cancer cells and coordinate broader immune responses. Unlike CAR-T therapies, which have demonstrated their greatest success in blood cancers, macrophage-based therapies are considered particularly promising for solid tumors.
However, translating macrophages into viable therapies has proven difficult. Mature macrophages are challenging to grow in large quantities, difficult to genetically modify and poorly suited for long-term storage and distribution. The USC-led team therefore turned its attention to an earlier stage in immune-cell development. The technology was published in a paper in Cell.
Scalable manufacturing
Using a defined chemical cocktail, the researchers succeeded in maintaining and expanding GMPs in the laboratory over extended periods while preventing them from maturing into other immune cell types. Even after prolonged cultivation, the cells retained their ability to generate functional macrophages and related immune cells.
According to senior author Qi-Long Ying, professor of stem cell biology and regenerative medicine at the Keck School of Medicine of USC, the findings challenge long-held assumptions about immune-cell biology. “The prevailing view has been that long-term self-renewal in the blood system is primarily a property of hematopoietic stem cells,” Ying said. “We found that, under the right conditions, GMPs can also self-renew while maintaining their identity and immune-cell generating capacity.”
The ability to expand these progenitor cells at scale could create a renewable source for future cell therapies, potentially reducing manufacturing complexity and cost. Independent validation by researchers at Stanford University confirmed the long-term maintenance and genetic engineering of GMPs, strengthening confidence in the platform’s translational potential.
Off-the-shelf immunotherapies
The researchers also demonstrated that GMPs can be genetically modified to function as cancer-fighting therapies. In the study, both mouse and human GMPs were engineered with chimeric antigen receptors (CARs), enabling them to recognize specific markers on tumor cells. The team added a second genetic modification designed to stimulate other immune cells and amplify anti-tumor responses. Importantly, this immune-activating signal remained effective even when donor and recipient immune systems were not fully matched.
That characteristic could pave the way for off-the-shelf therapies produced from donor cells rather than being individually manufactured for each patient, a process that currently limits the scalability of many cell-based treatments. When tested in animal models of blood cancers and solid tumors, engineered GMPs slowed disease progression. The strongest effects were observed in cells carrying both the CAR construct and the additional immune-activating signal. Unlike mature macrophages, which are often rapidly cleared from the body, the engineered GMPs established themselves in the bone marrow and continuously generated new therapeutic immune cells.
Beyond oncology
The platform’s potential may extend beyond cancer treatment. In a mouse model of chronic granulomatous disease, a rare inherited immune disorder, engineered GMPs restored the animals’ ability to combat bacterial infections. According to the researchers, the findings highlight the importance of selecting the right developmental stage of immune cells when designing next-generation immunotherapies.
While clinical application remains several years away, the study provides evidence that renewable, engineerable immune progenitor cells could become a versatile foundation for future cell therapies. If confirmed in human studies, the approach could help address one of the major bottlenecks in immunotherapy: delivering scalable, standardized treatments that are readily available when patients need them.
