Scientists at the University of Southern California (USC) have discovered a way to produce a potentially renewable supply of cancer-fighting immune cells, opening a promising new direction for cancer treatment. By working with immature cells that can develop into powerful immune defenders, the researchers have created a system capable of generating large numbers of genetically engineered cells that recognize tumors and help activate the body's natural defenses.
The breakthrough, described in a study published in Cell, could help overcome some of the biggest obstacles facing cancer immunotherapy, including the difficulty of manufacturing enough immune cells and keeping them active in the body. In experiments involving mice, the engineered cells established themselves in bone marrow, produced new immune cells, and slowed the progression of both blood cancers and solid tumors.
The USC Stem Cell-led team focused on a type of immature immune cell called granulocyte-monocyte progenitors (GMPs). These cells normally develop into macrophages and other immune cells that protect the body from infections and participate in immune responses. The researchers found that GMPs could be grown extensively in the laboratory while retaining their ability to develop into functioning immune cells. They could also be genetically modified to recognize specific cancer markers and strengthen broader immune responses.
"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, professor of stem cell biology and regenerative medicine at the Keck School of Medicine of USC.
Scientists Discover a Surprising Ability in Immune Cell Precursors
Beyond its potential applications in cancer treatment, the discovery challenges a long-standing understanding of how blood and immune cells develop.
Stem cells are known for their ability to self-renew, meaning they can repeatedly divide while maintaining their original properties. In the blood-forming system, this ability has traditionally been associated primarily with hematopoietic stem cells, which can produce all the major types of blood and immune cells.
Progenitor cells, by contrast, are further along in development and are already committed to producing a more limited range of cells. They are generally thought to have less capacity for long-term self-renewal.
The USC researchers demonstrated that GMPs can retain this ability under carefully controlled laboratory conditions. Rather than quickly maturing into other cell types, the progenitors continued multiplying while preserving their identity and their capacity to generate 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," said 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 could be especially important for developing treatments that require large, reliable supplies of genetically engineered immune cells.
Why Macrophages Could Be Powerful Weapons Against Cancer
Macrophages are among the immune system's most versatile defenders. Their name comes from Greek words meaning "big eaters," reflecting their ability to surround and engulf bacteria, damaged cells, and other unwanted material.
They also help coordinate immune responses by sending signals that influence the behavior of other immune cells. Some macrophages can enter tumors and attack cancer cells, making them attractive candidates for cancer immunotherapy.
One particularly promising application involves solid tumors, which include cancers that form masses in organs and tissues. Existing therapies based on engineered T cells have achieved their greatest successes against certain blood cancers, but treating solid tumors has proven more difficult.
Macrophages offer a potentially different approach because they naturally migrate into tissues and can penetrate tumors. However, turning them into practical treatments presents several challenges.
Once macrophages have fully matured, they are difficult to multiply in large quantities outside the body. They are also challenging to modify genetically and can be damaged during freezing and storage, complicating the production and distribution of cell therapies.
Another problem occurs after administration. Mature macrophages often collect in organs such as the lungs and liver instead of spreading widely throughout the body. Their relatively rapid disappearance can also limit how long a treatment remains effective.
To work around these limitations, the scientists decided to begin at an earlier stage of immune cell development.
Creating a Renewable Supply of Cancer-Fighting Immune Cells
Rather than trying to manufacture large numbers of mature macrophages, first author Shi Yue, MD, of Ying's laboratory and his colleagues concentrated on GMPs, the progenitor cells that can produce macrophages.
The researchers developed a precisely defined mixture of chemicals that allowed GMPs to survive and multiply for extended periods in the laboratory. The mixture prevented the cells from prematurely developing into mature immune cells, preserving a renewable population of progenitors.
Even after extensive laboratory expansion, the GMPs maintained the molecular characteristics that defined them. Importantly, they also retained the ability to develop into functional macrophages and other related immune cells when needed.
This approach could make it possible to manufacture large numbers of engineered immune cells from a starting population that can be continually expanded, instead of repeatedly collecting and preparing mature cells.
To confirm that the method could be reproduced, collaborators in the laboratory of Ravi Majeti, MD, PhD, at Stanford University independently demonstrated that GMPs could be maintained for extended periods and genetically engineered. Their results provided additional support for the reliability of the technique and its potential use in future cell therapies.
Majeti, Director of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University, noted: "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 Recognize and Attack Tumors
The team next investigated whether these expandable progenitor cells could be programmed to fight cancer.
They genetically engineered GMPs to carry a chimeric antigen receptor, or CAR. This engineered receptor allows immune cells to identify a particular molecular marker on the surface of cancer cells, helping direct their activity toward tumors.
CAR technology is already an important part of cancer immunotherapy, particularly in treatments that modify a patient's T cells to recognize and attack cancer. The USC researchers explored whether a similar strategy could be applied to GMPs, allowing them to generate engineered macrophages and other immune cells.
The scientists also equipped some of the progenitor cells with an additional immune-activating signal. This modification was designed to recruit and stimulate nearby immune cells, including T cells, which can help mount a stronger attack against cancer.
The added signal offered another potentially important advantage. It remained effective even when the immune characteristics of donor cells did not match those of the recipient.
That finding raises the possibility of developing off-the-shelf treatments using cells manufactured in advance from donors. Unlike personalized cell therapies, which must be prepared separately using each patient's own cells, such products could potentially be produced in larger batches and made available to multiple patients.
Engineered Cells Slow Cancer Progression in Mice
After successfully expanding and engineering GMPs from both mice and humans, the researchers investigated their therapeutic potential in mouse experiments.
When administered to mice, the progenitor cells established themselves in the bone marrow and other locations responsible for blood cell production. These environments provided places where the GMPs could generate additional engineered macrophages and related immune cells.
This was an important difference from treatments using mature macrophages. Instead of relying solely on immune cells that may disappear relatively quickly, the progenitors could provide a continuing source of replacement cells from within the body.
The strategy may therefore help overcome the rapid clearance that has limited macrophage therapies, including approaches evaluated in recent clinical trials.
The researchers tested the engineered cells in mice with blood cancers and solid tumors. GMPs carrying CAR receptors slowed disease progression in both types of cancer.
The effects were even stronger when the progenitors carried both CAR receptors and the additional signal designed to activate other immune cells. This combination improved the treatment's ability to stimulate a broader antitumor response.
Although these findings are encouraging, the cancer-treatment results remain preclinical. Further research will be needed to establish whether engineered GMPs can be used safely and effectively in people, particularly if they are intended to persist and produce immune cells over extended periods.
Potential Applications Beyond Cancer Treatment
The scientists also explored whether their approach could help treat conditions involving defective immune defenses.
In a separate mouse experiment, they studied chronic granulomatous disease, an inherited disorder that interferes with the ability of certain immune cells to kill harmful microbes. People with this condition are particularly vulnerable to recurrent bacterial and fungal infections because their immune cells cannot eliminate some pathogens effectively.
When the researchers administered GMPs to mice with the disorder, the cells restored the animals' ability to fight bacterial infection.
This result suggests that renewable, genetically engineered immune cell progenitors might eventually have applications beyond cancer, including treatments for inherited immune deficiencies and potentially infectious diseases.
The broader lesson, according to the researchers, is that the developmental stage of an immune cell may be just as important as the genetic modifications used to turn it into a treatment.
By engineering cells before they fully mature, scientists may be able to create therapies that are easier to manufacture, more adaptable, and capable of maintaining a continuing 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," said Ying.
About the Research
The study, published in Cell, is titled "Expansion and CAR engineering of granulocyte-monocyte progenitors for cellular immunotherapy."
Along with Ying, Yue, and Majeti, the 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 Stanford University School of Medicine; and Yingxiao Shi of Harvard Medical School and the Dana-Farber Cancer Institute.
Financial support came from 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.
Majeti also reported support from the Ludwig Institute for Cancer Research. Guo received funding through the California Institute for Regenerative Medicine Predoctoral Training Fellowship.
