USC Stem Cell scientists have developed a new method to generate a renewable and scalable supply of immune cell precursors that could help advance cancer immunotherapy and other treatments.
Published in a magazine cellThe study focuses on granulocyte-monocyte progenitor cells (GMPs), a type of progenitor cell that produces macrophages and several other immune cells. Macrophages play an important role in protecting the body from infectious diseases and are of increasing interest as potential tools for cancer treatment.
Researchers have shown that GMP can be broadly expanded in the lab and genetically engineered to recognize cancer cells while promoting a broader immune response.
“This study establishes a scalable and operable GMP platform for cellular immunotherapy and introduces a concept that we believe has the potential to have broad implications for both cancer immunotherapy and stem cell biology,” said corresponding author Qi-Long Ying, MD, professor of stem cell biology and regenerative medicine at the USC Keck School of Medicine.
One of the most important findings of this study concerns self-renewal, a property traditionally associated with stem cells. Self-renewal allows cells to divide repeatedly while maintaining their identity. Scientists generally do not believe that progenitor cells have such long-term capabilities.
“It is commonly believed that long-term self-renewal in the blood system is primarily a property of hematopoietic stem cells, which can generate all types of blood and immune cells,” Yin said. “We found that under the right conditions, GMP can also self-replicate and divide extensively while maintaining its identity and ability to produce functional immune cells. This provides a scalable starting point for designing cell therapies for cancer, infectious diseases, and potentially many other conditions.”
Why macrophage precursors are important
Macrophages are attractive candidates for cancer immunotherapy because they naturally invade tumors, consume cancer cells, and help orchestrate immune responses. Although T-cell therapy has had great success against blood cancers, macrophage-based therapies may offer particular benefits against solid tumors.
However, mature macrophages have several drawbacks as therapeutic products. They are difficult to grow in large quantities outside the body, difficult to genetically modify, and can be damaged during freezing or storage. It also tends to accumulate in organs such as the lungs and liver, rather than spreading widely throughout the body.
To overcome these obstacles, first author Shi Yue, MD, and colleagues in the Ying lab focused on GMPs, which are located early in the developmental pathway that generates macrophages.
Using a carefully defined chemical cocktail, the research team was able to prevent GMPs from maturing into other immune cell types and successfully maintain and grow GMPs over long periods of time in the laboratory.
Even after long-term proliferation, the cells preserved their molecular and cellular characteristics and continued to generate functional macrophages and other immune cells.
Researchers in the lab of Ravi Majeti, MD, PhD, at Stanford University, independently replicated the long-term maintenance and genetic engineering of GMP, further supporting the reliability and potential therapeutic value of the platform.
“This method for expanding and manipulating GMP, like expanding and manipulating T cells, opens the door to numerous translational applications,” said Majetti, director of Stanford University’s Institute for Stem Cell Biology and Regenerative Medicine. “We have already demonstrated that these cells can be manipulated to drive multiple powerful functions, and there is much more to explore.”
Developing GMP to fight cancer
Beyond its ability to grow long-term in the lab, GMP can also be genetically engineered for use as an immunotherapy.
In this study, the researchers equipped GMP with a chimeric antigen receptor (CAR) that allows the cells to recognize specific markers on cancer cells. The research team also added a second signal designed to stimulate tumor-fighting T cells and activate nearby immune cells that help strengthen the body’s natural defenses.
Importantly, this additional signal remains effective even when donor and recipient cells are immunologically mismatched. This increases the possibility of creating off-the-shelf treatments that are pre-generated from donor cells and used on many patients, rather than creating custom treatments for each individual.
The researchers expanded and manipulated both mouse and human GMPs and then tested them in mice. The cells successfully colonized the bone marrow and other hematopoietic tissues, where they continuously generated engineered macrophages and additional immune cells.
GMP maintained a continuous supply of these cells from the bone marrow, thereby avoiding the rapid loss that limits mature macrophage therapies, including those evaluated in recent clinical trials.
In mice with blood cancers and solid tumors, CAR-engineered GMP slowed disease progression. GMP, which carries both the CAR and additional immune activation signals, produced an even stronger advantage.
Possibilities beyond cancer
This platform has potential applications beyond oncology.
The researchers tested this approach in mice with chronic granulomatosis, an inherited immune disease. GMP treatment restored the animals’ ability to fight bacterial infections and also demonstrated the technology’s potential for immune deficiencies.
“Our study suggests that the future of immunotherapy may depend not only on the design of better CAR receptors, but also on the selection of the appropriate developmental stage of the cells,” said Dr. Yin.
About research
The paper inside cell The title is “Granulocyte-monocyte progenitor cell expansion and CAR engineering for cellular immunotherapy.”
In addition to Ying, Yue, and Majeti, additional authors include: Zheng Guo, Crystal Pan, Xueyuan A. Jing, Tai Nguyen, Jiaqi Tang, Yanpui Chan, Humberto Contreras-Trujillo, Du Jiang, Xue Yan, Hang Xiang, Xugen Liu, Xiao Wang, Ziyuan Wang, Natalie Shu, Daniel B. McKim, Rong Lu, and Chao Zhang USC; Litao Tao and Celia Bloom of the University of Southern California; Creighton University; Asili Ediriwickrema and Sebastian Kocharde of Stanford University School of Medicine; Yingxiao Shi of Harvard Medical School and Dana-Farber Cancer Institute;
This research was supported by the Zhongmei Group’s Chen Yong Foundation, a sponsored research project from Myelogene Inc., the LK Whittier Foundation, Eli and Edythe Broad Innovation Award, Ming Hsieh Institute for Research on Engineering Medicine for Cancer Award, USC SBIR/STTR Planning Award, Xia Research Fund, and Wu & Jiang Research Fund. Mr. Majetti reported support from the Ludwig Cancer Institute, and Mr. Guo reported support from the California Institute for Regenerative Medicine Predoctoral Training Fellowship.
disclosure
Ying, Yue, Jing, Guo, Majeti, Zhang, Nguyen, and Tang are co-inventors on a patent related to this work, filed by USC and licensed to Myelogene Inc. Ying, Yue, Zhang and Majeti are co-founders of Myelogene Inc. Majeti is a member of Kodikaz Therapeutic Solutions, Pheast Therapeutics, Prelude Therapeutics, Mubadala Capital, Acleus Therapeutics, Sequentify, BMS, and Bectas Therapeutics. Majeti is a co-founder and equity owner of Pheast Therapeutics.
