USC Scientists Unlock Renewable Supply of Cancer-Fighting Immune Cells via GMP Platform
核心洞察
USC-led research published in Cell demonstrates that granulocyte-monocyte progenitors (搜索) (GMPs) can be extensively expanded and genetically engineered in the laboratory for cancer immunotherapy.
The study overturns the prevailing view that long-term self-renewal is exclusive to hematopoietic stem cells, showing GMPs can self-renew while maintaining their identity.
CAR-engineered GMPs engrafted into bone marrow, continuously generating macrophages that delayed disease progression in mouse models of blood cancer and solid tumors.
A team led by researchers at the Keck School of Medicine of USC has demonstrated a scalable platform for generating a renewable supply of cancer-fighting immune cells, challenging a long-held tenet of stem cell biology in the process. Published in Cell, the study shows that granulocyte-monocyte progenitors (搜索) (GMPs)—cells already committed to producing macrophages and other immune cells—can be extensively expanded in the laboratory and genetically engineered to target tumors while stimulating broader immune responses.
"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," said corresponding author Qi-Long Ying, MD, PhD, professor of stem cell biology and regenerative medicine at the Keck School of Medicine of USC.
Challenging the Stem Cell Dogma
A central finding of the research concerns self-renewal, the ability of cells to divide repeatedly while preserving their identity—a property traditionally attributed exclusively to stem cells. Progenitor cells like GMPs were not thought to possess this long-term capability.
"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," said Ying. "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."
Using a carefully defined chemical cocktail, first author Shi Yue, MD, and colleagues prevented GMPs from maturing into other immune cell types, enabling their long-term maintenance and expansion. Even after prolonged growth, the cells preserved their molecular and cellular characteristics and continued generating functional macrophages.
Independent Validation at Stanford
The robustness of the platform was independently confirmed by collaborators in the laboratory of Ravi Majeti, MD, PhD, at Stanford University, who reproduced the long-term maintenance and genetic engineering of GMPs.
Majeti, Director of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University, noted: "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."
Why Macrophage Precursors Matter
Macrophages are appealing candidates for cancer immunotherapy because they naturally infiltrate tumors, engulf cancer cells, and help coordinate immune responses. While T-cell therapies have achieved major success against blood cancers, macrophage-based approaches may offer particular advantages against solid tumors.
However, mature macrophages present significant manufacturing challenges: they are difficult to expand to large numbers outside the body, hard to genetically engineer, and vulnerable to damage during freezing and storage. They also tend to accumulate in organs such as the lungs and liver rather than distributing widely. By targeting GMPs—which sit earlier in the developmental pathway—the researchers circumvented these obstacles.
Engineering GMPs for Cancer Immunotherapy
The team equipped GMPs with a chimeric antigen receptor (CAR), enabling the cells to recognize a specific marker on cancer cells. They also added a second signal designed to activate nearby immune cells that stimulate tumor-fighting T cells and strengthen the body's natural defenses. Importantly, this additional signal remains effective even when donor and recipient cells are immunologically mismatched, raising the possibility of off-the-shelf therapies manufactured in advance from donor cells.
After expanding and engineering both mouse and human GMPs, the researchers tested them in mice. The cells successfully engrafted into the bone marrow and other blood-forming tissues, where they continuously generated engineered macrophages and additional immune cells. Because the GMPs maintained an ongoing supply from the bone marrow, they avoided the rapid clearance that has limited mature macrophage therapies, including those evaluated in recent clinical trials.
In mice with blood cancers and solid tumors, CAR-engineered GMPs slowed disease progression. GMPs carrying both the CAR and the additional immune-activating signal produced even stronger benefits.
Beyond Oncology
The platform's potential extends beyond cancer. The researchers tested the approach in mice with chronic granulomatous disease (搜索), an inherited immune disorder. GMP treatment restored the animals' ability to fight bacterial infections, demonstrating applicability to immune deficiencies.
"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," said Ying.
The paper, titled "Expansion and CAR engineering of granulocyte-monocyte progenitors (搜索) for cellular immunotherapy," was supported by the Chen Yong Foundation of the Zhongmei Group, a sponsored research project from Myelogene Inc. (搜索), the L.K. Whittier Foundation, the Eli and Edythe Broad Innovation Award, and several other funding sources. Ying, Yue, Majeti, and several co-authors are co-inventors on patents related to this study, filed by USC and licensed to Myelogene Inc., of which Ying, Yue, Zhang, and Majeti are co-founders.