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Scientists at the University of Southern California (USC) Stem Cell have developed a renewable, expandable supply method for granulocyte-monocyte progenitors (GMPs), a type of progenitor cell that produces macrophages and other immune cells. Published in the journal Cell, the study details how these laboratory-expanded cells can be genetically modified to recognize cancer cells and boost broader immune responses, opening new pathways for cellular immunotherapy.
The Mechanics of Long-Term GMP Self-Renewal
According to corresponding author Qi-Long Ying, a professor of stem cell biology and regenerative medicine at the Keck School of Medicine of USC, the research challenges a long-standing biological consensus. Traditionally, scientists believed that long-term self-renewal in the blood system was an exclusive property of hematopoietic stem cells capable of generating any type of blood or immune cell. However, Ying notes that under specific chemical conditions, GMPs can also self-renew, dividing extensively while maintaining their cellular identity and ability to produce functional immune cells.
To achieve this, first author Shi Yue and colleagues in the Ying Lab utilized a carefully defined chemical cocktail. This mixture prevented GMPs from maturing into other immune cell types, allowing the research team to maintain and expand the progenitor cells over long periods in the laboratory. Independent researchers in the laboratory of Ravi Majeti at Stanford University successfully reproduced the long-term maintenance and genetic engineering of GMPs, validating the platform’s reliability.
Overcoming Limitations of Mature Macrophage Therapies
Macrophages naturally enter tumors, consume cancer cells, and help organize immune responses, making them strong candidates for oncology treatments. While T-cell therapies have achieved major success against blood cancers, macrophage-based therapies offer distinct advantages against solid tumors. Yet, mature macrophages present several therapeutic hurdles:
- They are difficult to grow in large quantities outside the body.
- They present significant challenges for genetic engineering.
- They can be damaged easily during freezing and storage.
- They tend to accumulate primarily in the lungs and liver rather than dispersing widely throughout the body.
By targeting GMPs—which sit earlier in the developmental pathway that produces macrophages—the USC team bypassed these obstacles. Even after extended growth phases, the cells preserved their molecular characteristics and continuously generated functional immune cells.
CAR Engineering and Off-The-Shelf Potential
Beyond laboratory expansion, the research team genetically engineered GMPs using a chimeric antigen receptor (CAR) to target specific markers on cancer cells. The team also incorporated a second signal designed to stimulate nearby immune cells, helping activate tumor-fighting T cells and strengthen natural defenses.
According to the study findings, this secondary signal remains effective even when donor and recipient cells are immunologically mismatched. This feature introduces the possibility of off-the-shelf therapies produced in advance from donor cells, eliminating the need to manufacture a custom treatment for each individual patient. When tested in mice with blood cancers and solid tumors, these CAR-engineered GMPs successfully settled into bone marrow and other blood-forming tissues, continuously generating engineered macrophages and slowing disease progression without the rapid loss observed in traditional mature macrophage treatments.
Applications Beyond Oncology
The platform’s utility may extend beyond cancer treatment. When tested in mice with chronic granulomatous disease—an inherited immune disorder—GMP treatment successfully restored the animals’ ability to fight bacterial infections, indicating potential applications for immune deficiencies.
Majeti, Director of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University, stated that the method opens the door to numerous translational applications comparable to T-cell expansion and engineering. Future clinical development will depend on testing these scalable platforms in broader preclinical models to evaluate safety and efficacy in humans.