By Budi Oetomo Narendra 
The groundbreaking research, led by scientists at the USC Stem Cell initiative, marks a significant advancement in the field of cellular immunotherapy, particularly for its potential application in challenging areas like solid tumors and chronic immune deficiencies. Published in the prestigious journal Cell, the study unveils a novel platform centered on granulocyte-monocyte progenitors (GMPs), a specific type of progenitor cell previously not recognized for its extensive self-renewal capabilities. This discovery opens new avenues for generating vast quantities of therapeutic immune cells, addressing a critical bottleneck in the development and delivery of advanced cell-based therapies.
A Novel Approach to Immunotherapy
The core of this innovation lies in the ability to cultivate and expand GMPs in laboratory settings. GMPs are the direct precursors to macrophages and several other crucial immune cell types. Macrophages, often described as the "first responders" of the immune system, are vital for recognizing and eliminating pathogens, clearing cellular debris, and orchestrating broader immune responses. Their natural ability to infiltrate tumors and engulf cancer cells has made them highly attractive candidates for next-generation cancer immunotherapies. However, harnessing macrophages for clinical use has historically been fraught with difficulties.
Traditional approaches to macrophage-based therapies have faced significant hurdles. Mature macrophages are notoriously difficult to grow in large numbers outside the body, challenging to genetically modify, and prone to damage during the necessary freezing and storage processes for therapeutic distribution. Furthermore, once infused, they tend to accumulate disproportionately in organs like the lungs and liver, limiting their widespread distribution and efficacy throughout the body, especially in solid tumors. These limitations have hampered the translation of promising macrophage research into widely available clinical treatments.
The USC team, spearheaded by first author Shi Yue, MD, and senior corresponding author Qi-Long Ying, MD, PhD, a professor of stem cell biology and regenerative medicine at the Keck School of Medicine of USC, circumvented these issues by focusing on GMPs. These cells reside earlier in the developmental pathway leading to macrophages, offering a more pliable and potent starting material. By developing a precisely defined chemical cocktail, the researchers successfully prevented GMPs from maturing prematurely into other immune cell types, thereby enabling their sustained maintenance and extensive expansion in laboratory cultures over extended periods. This breakthrough in ex vivo expansion represents a critical step towards creating an "off-the-shelf" cellular therapy product.
Unlocking Progenitor Cell Potential: The Revelation of Self-Renewal
One of the study’s most profound findings challenges long-held tenets in stem cell biology. Self-renewal, the capacity of a cell to divide repeatedly while preserving its original identity and developmental potential, has traditionally been almost exclusively attributed to true stem cells, such as hematopoietic stem cells (HSCs). HSCs are the foundational cells responsible for generating all blood and immune cell types throughout an organism’s lifespan. Progenitor cells, by contrast, were generally considered to have a more limited proliferative capacity and a commitment to differentiate into specific cell lineages, losing their self-renewal potential relatively quickly.
"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 revelation redefines our understanding of progenitor cell plasticity and offers immense practical implications. By demonstrating that GMPs, under specific environmental cues, can exhibit sustained self-renewal, the USC team has unlocked a virtually inexhaustible source of these crucial immune cell precursors. This provides an unprecedented advantage for manufacturing therapeutic cell products at a scale previously unimaginable for terminally differentiated macrophages or even other progenitor cell types. Even after extensive laboratory growth, the expanded GMPs maintained their distinct molecular and cellular characteristics, retaining their full capacity to generate functional macrophages and other immune cells upon appropriate differentiation signals.
The reliability and therapeutic potential of this GMP platform received independent validation from researchers in the laboratory of Ravi Majeti, MD, PhD, at Stanford University. Dr. Majeti’s team successfully reproduced the long-term maintenance and genetic engineering of GMPs, lending robust support to the USC findings and underscoring the platform’s robustness. "This method for the expansion and engineering of GMPs opens the door to numerous translational applications, much like T cell expansion and engineering," noted Dr. Majeti, who serves as Director of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University. "We have already demonstrated engineering of these cells to drive multiple potent functions, and there is a lot more to be explored."
Engineering Cells to Combat Cancer
Beyond their remarkable ability to expand extensively in vitro, the engineered GMPs demonstrated significant therapeutic promise, particularly in the context of cancer immunotherapy. The researchers equipped these GMPs with a chimeric antigen receptor (CAR), a synthetic protein that enables immune cells to specifically recognize and target markers found on cancer cells. This CAR technology has been transformative in the treatment of certain blood cancers, exemplified by the success of CAR-T cell therapies. However, CAR-T cells have shown limited efficacy against solid tumors due to challenges like poor tumor penetration, an immunosuppressive tumor microenvironment, and T-cell exhaustion. Macrophages, with their natural ability to infiltrate tumors and their distinct immune functions, offer a compelling alternative or complementary strategy for solid tumor treatment.
To further amplify the therapeutic effect, the USC team incorporated a second crucial signal into the engineered GMPs. This signal was designed to activate nearby immune cells, thereby stimulating tumor-fighting T cells and bolstering the body’s overall natural defenses. A critical aspect of this dual engineering strategy is that this additional immune-activating signal remains effective even when donor and recipient cells are immunologically mismatched. This feature is pivotal for developing "off-the-shelf" (allogeneic) therapies. Unlike autologous therapies, which require custom-made treatments from each patient’s own cells, off-the-shelf products can be manufactured in advance from healthy donor cells, stored, and readily administered to many patients. This dramatically reduces manufacturing costs, shortens treatment timelines, and enhances accessibility for a broader patient population, overcoming a major logistical and economic barrier in current cell therapies.
The researchers rigorously tested their expanded and engineered GMPs, derived from both mouse and human sources, in various mouse models. Upon administration, the engineered GMPs successfully engrafted into the bone marrow and other blood-forming tissues of the recipient mice. Crucially, from these hematopoietic niches, they continuously generated a steady supply of engineered macrophages and other immune cells. This sustained production of therapeutic cells from the bone marrow effectively circumvented the rapid loss that has plagued mature macrophage therapies, including those evaluated in recent clinical trials, which often require repeated dosing or suffer from short-lived effects.
In mouse models of both blood cancers and solid tumors, the CAR-engineered GMPs demonstrated a significant ability to slow disease progression. Even more compelling results were observed when GMPs carrying both the CAR and the immune-activating signal were deployed, producing even stronger anti-tumor benefits. These findings underscore the potential of this platform to not only directly target cancer cells but also to orchestrate a more robust and sustained systemic immune response against malignancies.
Beyond Oncology: Broader Therapeutic Horizons
The implications of the USC team’s GMP platform extend far beyond the realm of cancer. The researchers explored its utility in a model of chronic granulomatous disease (CGD), an inherited immune disorder characterized by the inability of phagocytes (including macrophages) to produce reactive oxygen species essential for killing certain bacteria and fungi. This deficiency leaves affected individuals highly susceptible to severe and recurrent infections. In mice with CGD, GMP treatment successfully restored the animals’ ability to effectively fight bacterial infections. This demonstration highlights the technology’s broad potential for addressing various immune deficiencies and other conditions where a robust and functional supply of specific immune cells is critical.
The ability to generate a renewable source of GMPs that can be engineered for specific functions opens doors for treating a wide array of diseases, including severe autoimmune disorders, chronic infectious diseases, and even regenerative medicine applications where immune modulation is desired. The concept of using a progenitor cell stage that can self-renew and then differentiate into desired functional cells presents a paradigm shift in how cell therapies are conceptualized and manufactured.
"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 emphasized. This statement encapsulates the core message of the research: that optimizing the cellular starting material is as crucial as refining the genetic engineering itself for maximizing therapeutic efficacy and sustainability.
Background and Context of Immunotherapy
The development of this GMP platform comes at a pivotal time in medical history, following decades of intense research into harnessing the body’s own immune system to fight disease. Immunotherapy, particularly in oncology, has revolutionized the treatment landscape for many cancers, offering hope where traditional treatments like chemotherapy and radiation often fall short. The first major breakthrough came with checkpoint inhibitors, drugs that block proteins that normally keep immune cells in check, thereby "releasing the brakes" on the immune system to attack cancer.
Subsequently, CAR-T cell therapy emerged as a personalized medicine marvel. Approved by the FDA in 2017, CAR-T therapy involves extracting a patient’s T cells, genetically engineering them in the lab to express a CAR that recognizes cancer cells, expanding these modified T cells, and then infusing them back into the patient. While CAR-T cells have achieved remarkable success rates in certain blood cancers like leukemia and lymphoma, leading to durable remissions, they face significant limitations. These include their high cost (often hundreds of thousands of dollars per treatment), the complex and lengthy manufacturing process (taking weeks), the potential for severe side effects (cytokine release syndrome, neurotoxicity), and crucially, their generally poor performance against solid tumors, which constitute the vast majority of human cancers.
Macrophages, unlike T cells, are professional phagocytes that naturally infiltrate various tissues, including the often-dense and immunosuppressive microenvironment of solid tumors. They are also highly plastic, meaning they can adopt different functional states (e.g., pro-inflammatory M1-like macrophages that kill tumors, or anti-inflammatory M2-like macrophages that promote tumor growth and repair). The challenge has been to re-educate and empower macrophages to consistently adopt a tumor-fighting phenotype and to overcome the logistical hurdles of their therapeutic production. The USC research directly addresses these challenges by providing a scalable source of early-stage precursors that can be engineered to maintain their anti-tumor functions and avoid rapid degradation.
Expert Perspectives and Future Directions
The scientific community has reacted positively to the findings, recognizing the potential for a paradigm shift in cell therapy manufacturing and application. The independent validation by Stanford University researchers underscores the robustness and reproducibility of the method, which is a critical criterion for clinical translation.
The next crucial steps will involve further preclinical optimization and, eventually, clinical trials. Researchers will focus on refining the genetic engineering to target a wider array of cancer markers, exploring different immune-activating signals, and optimizing the delivery methods in more complex animal models. The goal will be to establish safety and efficacy data that support moving this technology into human trials. Given the "off-the-shelf" potential, the pathway to clinical translation could be accelerated compared to autologous therapies, potentially allowing for broader and faster patient access.
This research not only promises to expand the arsenal against cancer but also fundamentally contributes to our understanding of stem cell and progenitor cell biology. The discovery of self-renewal in GMPs may prompt a re-evaluation of other progenitor populations, potentially uncovering similar hidden potentials that could be harnessed for various therapeutic applications. The broader implications for regenerative medicine, infectious disease, and immunology are immense, suggesting a future where complex cellular therapies are more accessible, affordable, and effective for a wider range of debilitating conditions.
About the Study
The full research paper, titled "Expansion and CAR engineering of granulocyte-monocyte progenitors for cellular immunotherapy," was published in the journal Cell.
Key contributors to this study, in addition to Drs. Ying, Yue, and Majeti, include 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; 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.
The extensive work was supported by several organizations 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.
Disclosures
It is noted that several key researchers involved in this study, including Drs. Ying, Yue, Jing, Guo, Majeti, Zhang, Nguyen, and Tang, are co-inventors on patents related to this groundbreaking work. These patents have been filed by USC and subsequently licensed to Myelogene Inc. Furthermore, Drs. Ying, Yue, Zhang, and Majeti are also identified as co-founders of Myelogene Inc. Dr. Majeti holds advisory board positions with several biotechnology and pharmaceutical companies, including Kodikaz Therapeutic Solutions, Pheast Therapeutics, Prelude Therapeutics, Mubadala Capital, Aculeus Therapeutics, Sequentify, BMS, and Bectas Therapeutics. He is also a co-founder and equity holder of Pheast Therapeutics. These disclosures highlight the potential for commercialization and further development of this promising technology.
