By Budi Oetomo Narendra 
Scientists at the USC Stem Cell laboratory have unveiled a groundbreaking method for generating a renewable and extensively expandable supply of immune cell precursors, a discovery poised to significantly advance cancer immunotherapy and a broad spectrum of other medical treatments. Published in the prestigious journal Cell, this innovative research centers on granulocyte-monocyte progenitors (GMPs), a specific type of progenitor cell that serves as the genesis for macrophages and several other crucial immune cells. Macrophages, known for their vital role in the body’s defense against infections, have increasingly garnered attention as potent tools in the fight against cancer, particularly solid tumors that have proven recalcitrant to existing immunotherapies.
Redefining Progenitor Cell Potential: A Paradigm Shift
The study’s most compelling finding challenges a long-held tenet in stem cell biology: the inherent capacity for self-renewal. Traditionally, long-term self-renewal, the ability of cells to divide repeatedly while meticulously preserving their identity, has been almost exclusively attributed to true stem cells, such as hematopoietic stem cells (HSCs), which are responsible for generating all blood and immune cell types. Progenitor cells, by contrast, were largely considered to possess a more restricted differentiation potential and a finite capacity for division.
However, the USC team, led by corresponding author Qi-Long Ying, MD, PhD, a distinguished professor of stem cell biology and regenerative medicine at the Keck School of Medicine of USC, demonstrated that under precisely defined laboratory conditions, GMPs exhibit robust self-renewal capabilities. "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," Dr. Ying explained. "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." This discovery fundamentally redefines our understanding of progenitor cell biology and opens up vast new possibilities for therapeutic applications.
Addressing the Immunotherapy Frontier: The Promise of Macrophages
The landscape of cancer treatment has been dramatically reshaped by immunotherapy, particularly T-cell-based approaches like CAR-T cell therapy. These therapies have achieved remarkable successes, especially against certain blood cancers such, as acute lymphoblastic leukemia and lymphomas, where response rates have been groundbreaking. However, CAR-T therapies face significant hurdles when it comes to solid tumors, which constitute approximately 90% of all human cancers. The complex, immunosuppressive microenvironment of solid tumors often renders T-cells ineffective, limiting their infiltration and sustained activity. Furthermore, the autologous nature of current CAR-T therapies, requiring genetically engineered cells from each individual patient, makes them incredibly expensive, time-consuming to manufacture (often several weeks), and inaccessible to many. The cost of a single CAR-T treatment can often exceed $400,000, not including associated medical expenses.
Macrophages present an attractive alternative or complementary strategy for cancer immunotherapy. These versatile immune cells naturally infiltrate tumor tissues, where they can directly engulf cancer cells through phagocytosis, present antigens to activate other immune cells, and modulate the tumor microenvironment. Their inherent ability to navigate and persist within solid tumors makes them particularly appealing candidates for addressing the challenges faced by T-cell therapies in these complex malignancies.
Despite their therapeutic promise, leveraging mature macrophages for treatment has encountered substantial practical difficulties. They are notoriously challenging to expand in large numbers outside the body, making the production of sufficient therapeutic doses problematic. Genetic engineering of mature macrophages is also complex, and they are susceptible to damage during the crucial processes of freezing and storage. Moreover, when administered systemically, mature macrophages tend to accumulate predominantly in organs such as the lungs and liver, rather than distributing widely throughout the body to reach diffuse tumor sites, thereby limiting their therapeutic efficacy.
A Novel Platform: Engineering and Expansion of Granulocyte-Monocyte Progenitors (GMPs)
To circumvent these significant obstacles, the research team, led by first author Shi Yue, MD, within Dr. Ying’s laboratory, shifted their focus to GMPs. These progenitor cells sit earlier in the developmental pathway that gives rise to mature macrophages, offering a potentially more pliable and robust starting material. The team embarked on a meticulous process to identify the precise conditions required to maintain and expand GMPs in vitro.
Their breakthrough involved the careful formulation of a specific chemical cocktail. This cocktail effectively prevented the GMPs from maturing prematurely into other immune cell types, thereby allowing them to be maintained and expanded over extended periods in laboratory cultures. Crucially, even after prolonged periods of growth and expansion, these cells retained their distinctive molecular and cellular characteristics. They consistently demonstrated the ability to differentiate into functional macrophages and other relevant immune cells upon appropriate signaling, confirming their integrity and therapeutic potential. This methodical approach established a reliable and reproducible method for generating vast quantities of these crucial precursor cells.
Independent Validation and Collaborative Reinforcement
The scientific rigor of this discovery was further strengthened by independent validation. Researchers in the laboratory of Ravi Majeti, MD, PhD, at Stanford University, successfully reproduced the long-term maintenance and genetic engineering of GMPs using the described methodology. This independent corroboration from another leading institution, particularly one with deep expertise in stem cell biology and regenerative medicine, significantly bolsters the platform’s reliability and underscores its potential therapeutic value.
Dr. Majeti, who serves as the Director of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University, emphasized the far-reaching implications of this work. "This method for the expansion and engineering of GMPs opens the door to numerous translational applications, much like T cell expansion and engineering," he stated. "We have already demonstrated engineering of these cells to drive multiple potent functions, and there is a lot more to be explored." This collaborative validation reinforces the robust nature of the USC team’s findings and points towards a collaborative future in advancing this technology.
Pre-Clinical Success: Transforming Cancer Treatment in Models
Beyond their remarkable expandability and stability in the laboratory, GMPs proved to be highly amenable to genetic engineering, making them ideal candidates for advanced immunotherapies. In this study, the USC researchers demonstrated the sophisticated engineering of GMPs to specifically target cancer cells. They equipped the GMPs with a chimeric antigen receptor (CAR), a synthetic protein that enables immune cells to recognize and bind to a specific marker expressed on the surface of cancer cells. This CAR technology, akin to that used in successful CAR-T therapies, directs the GMP-derived cells to identify and attack malignant cells.
Taking their innovation a step further, the team incorporated a second crucial signal into the engineered GMPs. This additional signal was designed to activate nearby immune cells, thereby orchestrating a broader and more robust immune response that helps stimulate tumor-fighting T cells and strengthens the body’s intrinsic anti-cancer defenses. A particularly significant aspect of this dual-signal approach is its efficacy even when donor and recipient cells are immunologically mismatched. This feature holds immense promise for the development of "off-the-shelf" therapies – standardized treatments produced in advance from donor cells that can be administered to a wide range of patients, eliminating the need for individualized, patient-specific cell manufacturing and dramatically improving accessibility and reducing costs.
After successful expansion and engineering of both mouse and human GMPs, the researchers meticulously tested these modified cells in mouse models. The results were highly encouraging. The engineered GMPs successfully engrafted into the bone marrow and other blood-forming tissues of the mice, establishing a continuous and self-renewing supply of engineered macrophages and other immune cells. This sustained production of therapeutic cells from the bone marrow effectively addressed a critical limitation observed in previous mature macrophage therapies, which often suffered from rapid cell loss and limited persistence in the body.
In mice afflicted with various cancers, including both blood cancers and solid tumors, the CAR-engineered GMPs demonstrated a significant ability to slow disease progression. Furthermore, the GMPs carrying both the CAR and the additional immune-activating signal produced even more potent anti-tumor benefits, highlighting the synergistic potential of their multi-pronged engineering strategy. These pre-clinical results provide a strong foundation for future translational research and ultimately, human clinical trials.
Beyond Oncology: Expanding Therapeutic Horizons
The potential applications of this GMP platform extend far beyond the realm of oncology. The inherent ability to generate a renewable supply of functional immune cells opens doors for treating a wide array of diseases characterized by immune deficiencies or dysregulation. To explore this broader potential, the researchers applied their approach to mouse models of chronic granulomatous disease (CGD).
Chronic granulomatous disease is a rare, inherited primary immunodeficiency disorder affecting approximately 1 in 200,000 to 250,000 people. Individuals with CGD have phagocytes (including macrophages) that are unable to produce superoxide, a crucial component of the immune system’s arsenal for killing certain bacteria and fungi. This defect renders patients highly susceptible to severe, recurrent, and life-threatening bacterial and fungal infections, often requiring lifelong prophylactic antibiotics and antifungals, and in some severe cases, hematopoietic stem cell transplantation. In the mouse models of CGD, treatment with engineered GMPs successfully restored the animals’ ability to effectively fight bacterial infections. This compelling result unequivocally demonstrates the broad therapeutic potential of the technology for immune deficiencies and underscores its versatility.
"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," Dr. Ying remarked, encapsulating the profound implications of their findings for the entire field of cellular therapy.
Scientific and Clinical Implications: A New Era for Immunotherapy
The discovery that GMPs possess long-term self-renewal capabilities under specific conditions marks a significant advance in stem cell biology. It challenges the conventional hierarchy of hematopoietic differentiation and suggests that progenitor cells may harbor more plasticity and regenerative potential than previously understood. This finding could lead to a re-evaluation of how various progenitor populations are characterized and utilized in regenerative medicine.
From a clinical perspective, the development of a scalable, engineerable GMP platform represents a crucial step towards realizing the full potential of macrophage-based immunotherapies. The ability to produce large quantities of these precursor cells reliably and cost-effectively, coupled with their capacity for precise genetic modification and sustained in vivo activity, addresses many of the limitations that have hampered previous macrophage-centric approaches. The "off-the-shelf" potential, facilitated by the dual-signal engineering strategy, promises to democratize access to advanced immunotherapies, making them more affordable and readily available to a broader patient population. This could significantly impact healthcare systems globally, reducing the economic burden associated with highly personalized treatments.
Furthermore, the successful application of this technology in models of chronic granulomatous disease highlights its versatility beyond cancer. It paves the way for potential treatments for other inherited immune disorders, infectious diseases, and even autoimmune conditions where modulating macrophage function could be therapeutically beneficial. The platform’s ability to continuously replenish functional immune cells from the bone marrow represents a powerful strategy for long-term therapeutic effects, a critical advantage in chronic diseases.
The Research Team and Funding
The seminal paper, titled "Expansion and CAR engineering of granulocyte-monocyte progenitors for cellular immunotherapy," was published in Cell. In addition to Dr. Qi-Long Ying and Dr. Shi Yue, key contributors included Zheng Guo, Crystal Pan, Xueyuan A. Jing, Tai Nguyen, Jiaqi Tang, Yanpui Chan, Humberto Contreras-Trujillo, Du Jiang, Xue Yan, Hang Xiang, Xugeng Liu, Xiao Wang, Ziyuan Wang, Natalie Shu, Daniel B. McKim, Rong Lu and Chao Zhang from USC. Collaborators also included Litao Tao and Celia Bloom from Creighton University; Asiri Ediriwickrema and Sebastian Koschade from Stanford University School of Medicine; and Yingxiao Shi from Harvard Medical School and the Dana-Farber Cancer Institute.
This pioneering work received substantial support from various institutions and foundations, including the Chen Yong Foundation of the Zhongmei Group, a sponsored research project from Myelogene Inc., the L.K. Whittier Foundation, the Eli and Edythe Broad Innovation Award, the Ming Hsieh Institute for Research on Engineering Medicine for Cancer Award, the USC SBIR/STTR Planning Award, the Xia Research Fund, and the Wu & Jiang Research Fund. Dr. Majeti’s contributions were supported by the Ludwig Institute for Cancer Research, and Zheng Guo received support from the California Institute for Regenerative Medicine Predoctoral Training Fellowship.
Transparency and Disclosures
In the interest of transparency and to disclose potential conflicts of interest, it is noted that several key researchers involved in this study hold patents and affiliations related to the developed technology. Dr. Ying, Dr. Yue, Jing, Guo, Dr. Majeti, Zhang, Nguyen, and Tang are co-inventors on patents related to this study, which have been filed by USC and subsequently licensed to Myelogene Inc. Furthermore, Dr. Ying, Dr. Yue, Zhang, and Dr. Majeti are co-founders of Myelogene Inc. Dr. Majeti also serves on the Advisory Boards of Kodikaz Therapeutic Solutions, Pheast Therapeutics, Prelude Therapeutics, Mubadala Capital, Aculeus Therapeutics, Sequentify, BMS, and Bectas Therapeutics, and is a co-founder and equity holder of Pheast Therapeutics. These disclosures are standard practice in scientific research and provide context for the commercialization potential of the innovation.
The advancements pioneered by the USC Stem Cell team represent a significant leap forward in cellular immunotherapy and stem cell biology. By unlocking the self-renewal potential of GMPs and developing a robust platform for their expansion and engineering, these scientists have laid the groundwork for a new generation of scalable, accessible, and highly effective treatments for cancer, immune deficiencies, and potentially many other challenging diseases. The path forward will involve rigorous pre-clinical development and, ultimately, human clinical trials to translate this profound scientific discovery into life-saving therapies.
