The breakthrough, which was detailed in a comprehensive study published in the esteemed scientific journal Cell, addresses and could ultimately help overcome some of the most formidable obstacles currently facing cancer immunotherapy. Among these major hurdles are the severe difficulties associated with manufacturing a sufficient number of functional immune cells on demand and keeping those cells active and viable once inside the human body. In preclinical experiments involving mice, these engineered cells successfully established themselves within the bone marrow, continuously produced new generations of functional immune cells, and demonstrably slowed the clinical progression of both aggressive blood cancers and stubborn solid tumors.
Unlocking the Potential of Immune Cell Precursors
The research team, led by investigators at the USC Stem Cell initiative, concentrated their efforts on a specific type of immature immune cell known as granulocyte-monocyte progenitors, or GMPs. Under normal physiological circumstances, these specialized progenitor cells develop into macrophages and various other vital immune cells that actively protect the body from invading pathogens, bacterial threats, and systemic infections, while also participating in broader immune responses. Through meticulous experimentation, the researchers discovered that GMPs could be grown extensively within a controlled laboratory environment while successfully retaining their critical ability to mature into fully functioning immune cells. Furthermore, the team found that these progenitor cells could be effectively modified using advanced genetic engineering techniques to recognize distinct cancer markers and significantly strengthen overall immune reactivity.
"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 the paper’s corresponding author, Qi-Long Ying, MD, PhD, who serves as a professor of stem cell biology and regenerative medicine at the Keck School of Medicine of USC.
Beyond its immediate and highly promising applications in the field of oncology, this remarkable scientific discovery challenges a long-standing, fundamental understanding of how human blood and immune cells develop over time. In cellular biology, stem cells are widely recognized for their remarkable ability to self-renew—a biological property meaning they can repeatedly divide while consistently maintaining their original, uncommitted properties. Within the complex blood-forming system, this unique self-renewing capacity has historically been attributed primarily, if not exclusively, to hematopoietic stem cells, which possess the capability to produce every major type of blood and immune cell found in the body.
Progenitor cells, by contrast, are situated further along the developmental pathway and are traditionally viewed as being already committed to producing a much more limited, restricted range of downstream cell types. Consequently, they have generally been thought to possess a sharply diminished capacity for long-term self-renewal. However, the USC research team brilliantly demonstrated that GMPs can retain this elusive self-renewing ability when placed under carefully controlled laboratory conditions. Rather than rapidly maturing and losing their proliferative capacity, these progenitor cells continued to multiply exponentially while simultaneously preserving their unique cellular identity and their inherent capacity to generate fully functional immune cells upon demand.
"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 fundamental realization could prove to be exceptionally vital for the future development of advanced medical treatments that require large, highly reliable, and reproducible supplies of genetically engineered immune cells.
Why Macrophages Stand Out as Potent Weapons Against Cancer
To fully appreciate the significance of the USC discovery, it is essential to examine the unique role that macrophages play within the human immune system. Macrophages rank among the body’s most versatile cellular defenders. Their name originates from ancient Greek roots translating literally to "big eaters," a descriptive moniker that perfectly captures their biological ability to actively surround, engulf, and digest bacteria, cellular debris, damaged tissues, and other unwanted foreign materials.
In addition to acting as physical clean-up crews, macrophages play a crucial orchestration role in coordinating complex immune responses. They achieve this by releasing targeted chemical signals that influence and direct the behavior of other neighboring immune cells. Certain specialized macrophages possess the remarkable ability to actively infiltrate the dense microenvironments of tumors and directly attack malignant cells, making them extraordinarily attractive candidates for the development of innovative cancer immunotherapies.
One particularly compelling application for macrophage-based therapies involves solid tumors—a broad category of cancers that form distinct masses in vital organs and tissues throughout the body. While existing cellular therapies based on engineered T cells have achieved remarkable clinical successes against certain liquid cancers like leukemias and lymphomas, treating solid tumors has historically proven to be considerably more difficult due to physical barriers and suppressive tumor microenvironments.
Macrophages offer a potentially revolutionary alternative approach because they naturally possess the ability to migrate deeply into peripheral tissues and can effectively penetrate the interior of solid tumors. Nevertheless, translating these natural cellular defenders into practical, scalable clinical treatments has presented researchers with a series of distinct biological challenges.
Once macrophages reach a state of full maturity, they become notoriously difficult to multiply in large quantities outside of the living body. Furthermore, mature macrophages are exceptionally challenging to modify using genetic engineering tools, and they frequently suffer severe structural damage during standard freezing and long-term storage procedures, which severely complicates the commercial manufacturing, preservation, and clinical distribution of cell-based therapies.
Another major hurdle materializes almost immediately after the cells are administered to a patient. Fully mature macrophages frequently sequester themselves in filtering organs such as the lungs and the liver rather than distributing widely throughout the body to target localized disease sites. Additionally, their relatively rapid disappearance from circulation can severely limit how long a given therapeutic intervention remains clinically effective.
In order to bypass these persistent limitations, the USC research team decided to approach the problem from an entirely different angle, focusing their attention on a much earlier, more malleable stage of immune cell development.
Establishing a Renewable Supply of Progenitor Cells
Rather than attempting the arduous task of manufacturing and maintaining massive numbers of fully mature macrophages directly, first author Shi Yue, MD, working within Dr. Ying’s laboratory, along with his talented colleagues, concentrated their investigative efforts on GMPs—the exact progenitor cells that naturally give rise to macrophages and related lineages.
The researchers successfully formulated a precisely defined chemical mixture and culture environment that allowed GMPs to survive, thrive, and multiply continuously for extended periods within the laboratory setting. Crucially, this specialized chemical cocktail prevented the progenitor cells from prematurely differentiating into fully mature immune cells, thereby preserving a stable, highly renewable population of foundational precursors.
Even after undergoing extensive rounds of laboratory expansion, the engineered GMPs maintained all of the complex molecular characteristics that initially defined them. Most importantly, they faithfully retained their latent biological ability to develop into fully functional macrophages and other associated immune cells whenever the biological cues required it.
This innovative strategy could ultimately make it possible to manufacture industrial-scale quantities of engineered immune cells starting from a foundational population that can be continually expanded in a bioreactor, completely eliminating the need to repeatedly harvest, process, and prepare mature cells directly from individual patients.
To independently confirm that this novel manufacturing method was robust and highly reproducible, the USC team collaborated with the laboratory of Ravi Majeti, MD, PhD, at Stanford University. Researchers at Stanford independently demonstrated that GMPs could indeed be successfully maintained over extended periods and efficiently engineered with genetic modifications. Their independent results provided vital scientific support for the overall reliability of the technique and underscored its immense potential for translation into future human cell therapies.
Dr. Majeti, who serves as the Director of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University, highlighted the broader implications of the work: "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 Immune Cells to Target and Destroy Tumors
With a reliable and expandable source of progenitor cells established, the research team next set out to investigate whether these malleable precursors could be successfully programmed to actively seek out and destroy cancer cells.
To achieve this, the investigators genetically engineered the GMPs to express a chimeric antigen receptor, commonly referred to as a CAR. This specially designed artificial receptor equips the immune cells with the ability to lock onto a specific, pre-determined molecular marker located exclusively on the surface of cancer cells, thereby directing their destructive activity squarely toward malignant tumors.
While CAR technology has already become a cornerstone of modern cancer immunotherapy—most notably through therapies that modify a patient’s own T cells—the USC researchers pioneered the novel concept of applying a similar genetic strategy upstream to GMPs. This approach successfully enabled them to generate large cohorts of engineered macrophages and related immune cells equipped with targeted tumor-recognition capabilities.
In addition to the CAR modification, the scientists took the engineering process a step further by outfitting certain progenitor cells with an additional immune-activating signal. This supplementary genetic modification was purposefully engineered to recruit, stimulate, and rally nearby immune cells—including native T cells—which can collectively work to mount a much more robust, multi-pronged immune attack against the cancer.
This clever dual-modification strategy offered another potentially significant advantage: the added signal remained fully functional even when the immunological characteristics of the donor cells did not perfectly match those of the recipient organism. This critical finding raises the exciting possibility of developing standardized, "off-the-shelf" immunotherapeutic treatments manufactured well in advance using healthy donor cell lines. Unlike highly personalized cell therapies—which currently require separate, time-consuming preparation using each individual patient’s unique cells—such off-the-shelf products could theoretically be manufactured in large, standardized batches and made readily available to multiple patients in need.
Preclinical Success in Animal Models
After successfully expanding and genetically engineering GMPs derived from both murine and human sources, the researchers advanced their investigation to rigorous preclinical evaluations using mouse models.
When these engineered progenitor cells were administered to the test subjects, they successfully homed in and established themselves within the bone marrow and other primary anatomical niches responsible for natural blood cell production. These specialized microenvironments provided an ideal biological home where the transplanted GMPs could continuously manufacture fresh supplies of engineered macrophages and related immune cell progeny from within the living organism.
This capability represents a dramatic and crucial departure from traditional therapies utilizing mature macrophages. Rather than depending exclusively on a static infusion of mature cells that inevitably disappear from circulation relatively quickly, the progenitor-based approach provides a self-sustaining, continuing source of cellular replacement from deep inside the patient’s own body.
This self-replenishing strategy may therefore help solve the persistent problem of rapid cellular clearance that has historically limited the clinical effectiveness of macrophage therapies, including various experimental approaches evaluated in recent clinical trials.
The researchers rigorously tested the engineered GMPs in animal models afflicted with both aggressive blood cancers and stubborn solid tumors. The results were striking: GMPs carrying the specialized CAR receptors successfully slowed disease progression across both broad categories of cancer. Furthermore, the therapeutic effects were noticeably magnified when the progenitor cells were engineered to carry both the targeted CAR receptors and the additional immune-activating signal designed to recruit other components of the host immune system. This synergistic combination significantly enhanced the overall ability of the treatment to stimulate a broad, sustained antitumor response.
Although these laboratory findings are undeniably encouraging, researchers emphasize that the cancer-treatment results remain strictly preclinical at this stage. Substantial additional research, safety testing, and formal clinical evaluations will be required to determine whether engineered GMPs can be translated safely and effectively for use in human patients, particularly when designed to persist long-term and continuously generate immune cells inside the body.
Exploring Horizons Beyond Oncology
Beyond their immediate applications in cancer research, the USC scientists also explored whether their pioneering expansion and engineering platform could be harnessed to treat other complex medical conditions characterized by defective or compromised immune defenses.
In a separate series of controlled mouse experiments, the investigators focused on chronic granulomatous disease, a serious inherited genetic disorder that severely disrupts the ability of certain immune cells to generate the reactive molecules required to kill harmful microbes. Individuals afflicted with this condition are exceptionally vulnerable to recurrent, severe bacterial and fungal infections because their native immune cells cannot effectively eliminate specific pathogens.
When the researchers administered the engineered GMPs to mouse models representing the genetic disorder, the therapeutic cells successfully engrafted and restored the animals’ natural ability to effectively fight off dangerous bacterial infections.
This promising proof-of-concept result strongly suggests that renewable, genetically engineered immune cell progenitors might eventually find valuable clinical applications far beyond oncology, potentially paving the way for advanced treatments targeting inherited immune system deficiencies and a wide range of persistent infectious diseases.
According to the research team, the overarching lesson of the study is that the precise developmental stage of an immune cell may ultimately prove to be just as critical as the specific genetic modifications utilized to adapt it for therapy. By engineering cells early in their developmental lineage before they reach full maturity, scientists may unlock the ability to design advanced cellular therapies that are significantly easier to manufacture on an industrial scale, vastly more adaptable to diverse disease environments, and uniquely capable of sustaining a continuous supply of specialized defenders within the body.
"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 concluded.
The foundational study, titled "Expansion and CAR engineering of granulocyte-monocyte progenitors for cellular immunotherapy," was supported by a diverse coalition of research institutions and funding bodies. Alongside Dr. Ying, Dr. Yue, and Dr. Majeti, the international research team 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 of USC; Litao Tao and Celia Bloom of Creighton University; Asiri Ediriwickrema and Sebastian Koschade of the Stanford University School of Medicine; and Yingxiao Shi of Harvard Medical School and the Dana-Farber Cancer Institute.
Financial support for the extensive research project was provided by the Chen Yong Foundation of the Zhongmei Group, a sponsored research grant 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 reported receiving research support from the Ludwig Institute for Cancer Research, while researcher Zheng Guo received financial backing through the California Institute for Regenerative Medicine Predoctoral Training Fellowship.