TOKYO —

A groundbreaking discovery by researchers at the University of Southern California (USC) has unveiled a novel method for producing a potentially inexhaustible supply of immune cells engineered to combat cancer. This breakthrough, detailed in the prestigious journal Cell, centers on harnessing the remarkable self-renewal capabilities of immature immune cells, known as granulocyte-monocyte progenitors (GMPs). By meticulously cultivating and genetically modifying these progenitor cells, scientists have devised a system capable of generating vast quantities of specialized immune defenders poised to identify and neutralize tumors, thereby bolstering the body’s intrinsic defenses.

This pioneering work addresses some of the most significant hurdles in the field of cancer immunotherapy, particularly the challenges associated with manufacturing sufficient numbers of therapeutic immune cells and ensuring their sustained activity within the patient’s body. Preclinical studies conducted in mouse models have demonstrated that these engineered GMPs can effectively colonize bone marrow, continuously produce new immune cells, and significantly impede the progression of both hematological malignancies and solid tumors.

The Power of Progenitor Cells: A Paradigm Shift in Immune Cell Development

For decades, the scientific community has largely attributed the long-term self-renewal capacity within the hematopoietic system primarily to hematopoietic stem cells (HSCs). These are considered the ultimate progenitors, capable of differentiating into all major types of blood and immune cells. In contrast, progenitor cells, including GMPs, were understood to be more committed to specific cell lineages and possess a limited capacity for sustained self-replication. They were thought to be on a more defined trajectory toward maturation.

However, the USC-led team, under the guidance of Qi-Long Ying, MD, PhD, a professor of stem cell biology and regenerative medicine at the Keck School of Medicine of USC, has challenged this long-held dogma. Their research meticulously demonstrates that under carefully controlled laboratory conditions, GMPs can indeed exhibit remarkable self-renewal properties. Instead of rapidly differentiating into mature cell types, these progenitors were observed to multiply extensively while retaining their essential identity and their inherent ability to give rise to functional immune cells.

"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, the study’s corresponding author. "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 pivotal finding is particularly significant for the development of advanced cell therapies that demand a consistent and abundant supply of genetically modified immune cells. It suggests that the developmental stage of an immune cell may be as crucial as the specific genetic modifications employed for therapeutic purposes.

Macrophages: Versatile Defenders with Untapped Potential

Macrophages, derived from GMPs, are among the immune system’s most adaptable and powerful effector cells. Their name, originating from Greek words meaning "big eaters," accurately describes their primary function: engulfing and clearing pathogens, cellular debris, and other harmful substances. Beyond their phagocytic capabilities, macrophages play a critical role in orchestrating immune responses by releasing signaling molecules that modulate the behavior of other immune cells. Certain types of macrophages can infiltrate tumors, directly attacking cancer cells, making them highly attractive candidates for innovative cancer immunotherapies.

The potential of macrophages is particularly pronounced in the context of solid tumors, which represent a significant therapeutic challenge. While engineered T-cell therapies have achieved notable successes against certain blood cancers, effectively treating solid tumors has remained a formidable obstacle. Macrophages offer a promising alternative due to their natural migratory capacity into tissues and their ability to penetrate dense tumor masses.

Despite their inherent advantages, translating macrophages into effective therapeutic agents has been fraught with difficulties. Mature macrophages are notoriously hard to expand in large quantities ex vivo. Furthermore, they are challenging to genetically engineer, and their viability can be compromised during cryopreservation and storage, complicating manufacturing and distribution processes. Another clinical challenge is their tendency to accumulate in organs like the lungs and liver after administration, rather than dispersing effectively throughout the body. Their relatively short lifespan in circulation can also limit the duration of therapeutic benefit.

Engineering a Renewable Reservoir of Cancer-Fighting Cells

To circumvent these limitations, the USC research team strategically shifted their focus to an earlier stage of immune cell development: GMPs. Instead of attempting to mass-produce mature macrophages, the researchers, led by first author Shi Yue, MD, concentrated on these progenitor cells, which are the precursors to macrophages and other myeloid cells.

The scientists developed a precisely formulated cocktail of growth factors and signaling molecules that enabled GMPs to survive and proliferate for extended periods in the laboratory. This specialized culture environment prevented the premature differentiation of GMPs into mature immune cells, thus preserving a renewable and expandable population of progenitor cells. Crucially, even after extensive laboratory expansion, these GMPs maintained their defining molecular characteristics and, most importantly, their capacity to differentiate into functional macrophages and related immune cells upon demand.

This innovative approach offers a pathway to manufacture large numbers of genetically engineered immune cells from a foundational population that can be continuously expanded, eliminating the need for repeated collection and preparation of mature cells. The reproducibility and robustness of this technique were further validated by collaborators in the laboratory of Ravi Majeti, MD, PhD, at Stanford University. Independent experiments at Stanford confirmed that GMPs could be maintained ex vivo for extended periods and successfully genetically engineered, providing strong support for the reliability and potential clinical utility of this method.

Dr. Majeti, Director of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University, commented on the significance of the findings: "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."

Programming Immune Cells for Tumor Recognition and Attack

Having established a method for generating expandable and engineerable GMPs, the researchers then investigated their potential to be programmed for cancer immunotherapy. They employed a genetic engineering strategy, equipping the GMPs with a chimeric antigen receptor (CAR). This engineered receptor acts like a molecular key, enabling immune cells to recognize specific protein markers present on the surface of cancer cells, thereby directing their cytotoxic activity toward tumors.

CAR technology has already become a cornerstone of modern cancer immunotherapy, particularly in T-cell-based treatments that genetically modify a patient’s own T cells to target cancer. The USC researchers explored the feasibility of applying a similar CAR engineering approach to GMPs, with the aim of generating engineered macrophages and other myeloid cells that can effectively seek out and destroy cancer.

In a further enhancement, some of the engineered progenitor cells were also equipped with an additional immune-stimulating signal. This modification was designed to actively recruit and activate other immune cells in the vicinity, including T cells, thereby amplifying the overall antitumor immune response. This added signal proved to be particularly advantageous, as it remained effective even when the immune characteristics of the donor cells did not perfectly match those of the recipient.

This observation carries significant implications for the development of "off-the-shelf" cell therapies. Such treatments, manufactured in advance from donor cells, could potentially be produced in large batches and made readily available to multiple patients, offering a more accessible and cost-effective alternative to personalized cell therapies that require individual preparation for each patient.

Preclinical Success: Engineered Cells Slow Cancer Progression in Mice

Following successful expansion and genetic engineering of GMPs derived from both mouse and human sources, the researchers proceeded to evaluate their therapeutic efficacy in rigorous mouse experiments. Upon intravenous administration, these engineered progenitor cells demonstrated an ability to home to and establish themselves within the bone marrow and other sites critical for blood cell production. These niches served as reservoirs where the GMPs could continuously generate additional engineered macrophages and related immune cells.

This intrinsic ability to replenish the immune cell supply from within the body represents a significant departure from treatments relying solely on mature immune cells, which are often cleared from circulation relatively quickly. The progenitor cell strategy offers the potential to overcome the rapid clearance that has historically limited the effectiveness of macrophage-based therapies, including those evaluated in recent clinical trials.

The engineered GMPs were tested in mouse models bearing both blood cancers and solid tumors. In both scenarios, GMPs engineered with CAR receptors demonstrated a significant ability to slow disease progression. The therapeutic impact was even more pronounced when the progenitor cells carried both CAR receptors and the immune-activating signal, indicating that this combined approach fostered a more robust and comprehensive antitumor immune response.

While these preclinical findings are highly encouraging, it is important to note that they represent early-stage research. Further extensive investigation will be required to ascertain the safety and efficacy of engineered GMPs in human patients, particularly concerning their potential for long-term persistence and sustained immune cell production.

Beyond Cancer: Broadening the Horizon of Immunotherapy

The potential applications of this groundbreaking technology extend beyond cancer treatment. The researchers also explored whether their approach could be leveraged to address conditions characterized by defective immune defenses. In a separate series of experiments using a mouse model of chronic granulomatous disease (CGD), an inherited disorder that impairs the ability of certain immune cells to combat microbial infections, the team administered engineered GMPs. Mice with CGD are highly susceptible to recurrent bacterial and fungal infections due to their compromised ability to eliminate certain pathogens.

The administration of these GMPs successfully restored the animals’ capacity to fight bacterial infections, suggesting that renewable, genetically engineered immune cell progenitors could hold promise for treating inherited immune deficiencies and potentially a range of infectious diseases.

The overarching lesson from this research, according to the scientists, is that the developmental stage of an immune cell is as critical as the genetic modifications used to engineer it for therapeutic purposes. By intervening at an earlier, progenitor stage, scientists may be able to develop cell therapies that are not only easier to manufacture and more adaptable but also capable of providing a continuous and sustained supply of specialized immune defenders.

"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. This insight points toward a more nuanced and sophisticated approach to cellular immunotherapy, one that considers the intricate biology of immune cell development alongside genetic engineering advancements.

The research, published in Cell, was supported by a consortium of funding sources, 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. Additional support was provided to Dr. Majeti by the Ludwig Institute for Cancer Research, and Dr. Guo received funding through the California Institute for Regenerative Medicine Predoctoral Training Fellowship. The collaborative effort involved researchers from USC, Creighton University, Stanford University School of Medicine, and Harvard Medical School and the Dana-Farber Cancer Institute.