By Budi Oetomo Narendra 
This groundbreaking research, published in the esteemed journal Cell, introduces a novel approach to generate a robust and customizable supply of granulocyte-monocyte progenitors (GMPs). These GMPs are crucial precursor cells responsible for producing various immune cells, most notably macrophages, which are increasingly recognized for their potent capabilities in combating infections and, more recently, in targeting cancer. The study not only demonstrates the ability to extensively expand and genetically engineer these cells in the laboratory but also challenges long-held scientific views regarding the self-renewal capacity of progenitor cells, potentially redefining fundamental principles in stem cell biology.
The Unmet Need in Cancer Immunotherapy
Cancer remains a formidable global health challenge, with millions of new diagnoses and fatalities each year. According to the World Health Organization, cancer is a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020. While significant strides have been made in treatment modalities, including chemotherapy, radiation, and targeted therapies, immunotherapy has emerged as a particularly transformative field over the past decade.
One of the most celebrated successes in modern immunotherapy is Chimeric Antigen Receptor (CAR) T-cell therapy. This revolutionary treatment involves genetically engineering a patient’s own T cells to recognize and attack cancer cells. Since the first CAR-T cell therapies received FDA approval in 2017 for specific blood cancers like acute lymphoblastic leukemia and large B-cell lymphoma, they have shown remarkable efficacy, often leading to durable remissions in patients who had exhausted other treatment options. The global CAR-T cell therapy market size was valued at over $2 billion in 2022 and is projected to grow substantially, reflecting the profound impact of this technology.
However, CAR-T cell therapy faces several significant limitations. It is an incredibly complex, individualized, and expensive treatment, often costing hundreds of thousands of dollars per patient. The manufacturing process is lengthy, and patients must endure a waiting period while their cells are prepared. More critically, CAR-T therapies have largely struggled to achieve comparable success against solid tumors, which constitute about 90% of all cancers. The challenges in solid tumors include the hostile tumor microenvironment, poor T-cell infiltration, antigen heterogeneity, and the presence of immunosuppressive cells. This has spurred researchers to explore alternative immune cell types for therapy, with macrophages emerging as a promising candidate.
Macrophages: The Body’s Natural Tumor Fighters
Macrophages are large white blood cells that are a cornerstone of the innate immune system. They act as the body’s primary phagocytes, engulfing and digesting cellular debris, foreign substances, microbes, and cancer cells. Beyond their role as "scavengers," macrophages are crucial antigen-presenting cells, initiating adaptive immune responses, and orchestrating tissue repair and inflammation. Their natural ability to infiltrate tumors, consume cancer cells, and stimulate broader immune responses makes them highly appealing for cancer immunotherapy, especially for solid tumors where T cells often falter.
Despite their therapeutic potential, mature macrophages present several practical hurdles for clinical application. They are notoriously difficult to expand in large numbers ex vivo (outside the body), making large-scale manufacturing challenging. Genetic engineering of mature macrophages is also complex, and they are susceptible to damage during cryopreservation (freezing and storage). Furthermore, when administered, mature macrophages tend to accumulate predominantly in organs such as the lungs and liver, limiting their widespread distribution and efficacy in targeting distant tumors. These drawbacks have hindered the translation of macrophage-based therapies into widespread clinical use, necessitating a more robust and scalable approach.
A Paradigm Shift: Granulocyte-Monocyte Progenitors (GMPs) and Self-Renewal
The USC Stem Cell research team, led by Dr. Qi-Long Ying, MD, PhD, Professor of Stem Cell Biology and Regenerative Medicine at the Keck School of Medicine of USC, circumvented the limitations of mature macrophages by focusing on GMPs. These cells are positioned earlier in the developmental lineage that gives rise to macrophages and other immune cells like neutrophils and dendritic cells. The pivotal discovery lies in the ability to maintain and extensively expand these GMPs in the laboratory, a feat previously thought to be primarily reserved for hematopoietic stem cells (HSCs).
"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," explained Dr. 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."
This finding represents a significant re-evaluation of progenitor cell capabilities. Traditionally, progenitor cells were understood to have limited self-renewal capacity, primarily committed to a specific lineage and undergoing terminal differentiation after a finite number of divisions. The ability to induce long-term self-renewal in GMPs, while preserving their multipotency and functionality, unlocks unprecedented opportunities for cell therapy manufacturing. First author Shi Yue, MD, and his colleagues achieved this breakthrough by employing a carefully defined chemical cocktail, which successfully prevented the GMPs from maturing into other immune cell types, thus maintaining their progenitor state and allowing for prolonged expansion. Even after extensive laboratory growth, these expanded GMPs retained their molecular and cellular characteristics, consistently generating functional macrophages and other immune cells.
Independent Validation and Robustness
The reliability and therapeutic potential of this GMP platform were further underscored by independent validation. Researchers in the laboratory of Dr. Ravi Majeti, MD, PhD, Director of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University, successfully reproduced the long-term maintenance and genetic engineering of GMPs. This independent corroboration from a leading institution adds substantial weight to the scientific validity and potential translational value of the USC team’s findings.
Dr. Majeti emphasized the broad implications: "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."
Engineering GMPs to Combat Cancer: A Dual-Signal Approach
Beyond their remarkable expandability, the engineered GMPs demonstrated significant therapeutic potential in preclinical models. The researchers equipped the GMPs with a Chimeric Antigen Receptor (CAR), similar to those used in CAR-T cell therapy, enabling them to specifically recognize markers found on cancer cells. This CAR-engineered GMP then differentiates into CAR-macrophages within the body, which can specifically target and engulf tumor cells.
Crucially, the team also incorporated a second, distinct signal designed to activate nearby immune cells, thereby stimulating tumor-fighting T cells and amplifying the body’s natural defenses. This dual-signal approach represents an advanced strategy to overcome the immunosuppressive tumor microenvironment. A key advantage of this secondary signal is its effectiveness even when donor and recipient cells are immunologically mismatched. This feature is particularly significant as it paves the way for the development of "off-the-shelf" therapies—pre-manufactured cellular products derived from healthy donors that can be readily administered to many patients, circumventing the logistical and cost challenges associated with personalized, patient-derived cell therapies.
Preclinical Efficacy and Sustained Response
To assess their therapeutic potential, the researchers expanded and engineered both mouse and human GMPs and tested them in various mouse models of cancer. Upon administration, these engineered GMPs successfully engrafted into the bone marrow and other blood-forming tissues. From these endogenous reservoirs, they continuously generated a sustained supply of engineered macrophages and other immune cells. This continuous replenishment from the bone marrow addresses a critical limitation of previous mature macrophage therapies, which often suffered from rapid cell loss and limited persistence in the body, as observed in some clinical trials.
In mice harboring blood cancers and solid tumors, the CAR-engineered GMPs demonstrated a significant ability to slow disease progression. Even more promising results were observed when GMPs carried both the CAR and the additional immune-activating signal, leading to even stronger anti-tumor benefits. These findings underscore the synergistic potential of combining direct tumor targeting with broader immune system activation.
Beyond Oncology: Expanding Therapeutic Horizons
The utility of this innovative GMP platform extends beyond the realm of oncology. The researchers explored its potential in treating inherited immune disorders. In a mouse model of chronic granulomatous disease (CGD), a genetic disorder characterized by the inability of phagocytes to kill certain bacteria and fungi, GMP treatment successfully restored the animals’ ability to fight bacterial infections. This demonstration highlights the technology’s broad applicability for addressing various immune deficiencies, opening new avenues for regenerative medicine and immune restoration.
Dr. Ying concluded, "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." This statement encapsulates the profound insight of the research, emphasizing that cell fate and developmental plasticity are critical parameters for optimizing cellular immunotherapies.
Broader Implications and Future Outlook
The development of this scalable and engineerable GMP platform carries significant implications for the future of medicine. Scientifically, it challenges established paradigms in hematopoiesis and stem cell biology, expanding our understanding of progenitor cell self-renewal. Clinically, it offers a pathway to more accessible, effective, and potentially less toxic cell therapies for a wide range of diseases.
The "off-the-shelf" potential of GMP-derived therapies could dramatically reduce manufacturing costs and turnaround times, making advanced cell therapies available to a much broader patient population globally. This could democratize access to cutting-edge treatments that are currently limited by their complexity and expense. The ability to generate a sustained supply of engineered immune cells from bone marrow depots also addresses issues of cell persistence, a common challenge in many cell-based therapies.
While the preclinical data are highly encouraging, the next critical step will be to translate these findings into human clinical trials. This will involve rigorous testing to ensure safety and efficacy in patients, as well as overcoming manufacturing challenges to produce clinical-grade GMPs at scale. Regulatory bodies will also need to establish clear pathways for the approval of these novel cell products.
The involvement of Myelogene Inc., a company co-founded by several of the study’s key authors, underscores the commercial interest and potential for rapid development and eventual market availability of these therapies. As the field of cellular immunotherapy continues to evolve, the USC/Stanford breakthrough with GMPs represents a significant leap forward, offering renewed hope for patients battling cancer, infectious diseases, and debilitating immune disorders.
About the Study
The research paper, "Expansion and CAR engineering of granulocyte-monocyte progenitors for cellular immunotherapy," was published in the journal Cell. Key authors include Qi-Long Ying, Shi Yue, and Ravi Majeti, alongside a comprehensive team of researchers from USC, Stanford University School of Medicine, Creighton University, Harvard Medical School, and the Dana-Farber Cancer Institute.
This pivotal work received substantial financial backing from various organizations, 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. Additionally, Dr. Majeti received support from the Ludwig Institute for Cancer Research, and Dr. Guo was supported by the California Institute for Regenerative Medicine Predoctoral Training Fellowship.
Disclosures
Several of the contributing authors, including Drs. Ying, Yue, Jing, Guo, Majeti, Zhang, Nguyen, and Tang, hold co-inventor status on patents related to this study, which have been filed by USC and subsequently licensed to Myelogene Inc. Drs. Ying, Yue, Zhang, and Majeti are also identified as co-founders of Myelogene Inc. Dr. Majeti further maintains affiliations with various advisory boards, including Kodikaz Therapeutic Solutions, Pheast Therapeutics, Prelude Therapeutics, Mubadala Capital, Aculeus Therapeutics, Sequentify, BMS, and Bectas Therapeutics, and is a co-founder and equity holder in Pheast Therapeutics. These disclosures highlight the potential for commercial translation of this innovative research.
