USC Stem Cell scientists have developed a new method to create a renewable and scalable supply of immune cell precursors that could help advance cancer immunotherapy and other treatments.
Published in the magazine CellThe study focuses on granulocyte-monocyte progenitors (GMP), a type of progenitor cell that produces macrophages and several other immune cells. Macrophages play a key role in defending the body against infections and have attracted increasing interest as potential tools for cancer treatment.
The researchers showed that GMPs can be widely scaled up in the laboratory and genetically modified to recognize cancer cells while stimulating broader immune responses.
“The study establishes a scalable and configurable 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.
One of the most significant findings of the study has to do with self-renewal, a characteristic traditionally associated with stem cells. Self-renewal allows cells to divide repeatedly while maintaining their identity. In general, scientists have not considered progenitor cells to possess this long-term capacity.
“The prevailing view has been that long-term self-renewal in the blood system is mainly a property of hematopoietic stem cells that can generate any type of blood or immune cell,” Ying said. “We found that, under the right conditions, GMPs can also self-renew, dividing widely while maintaining their identity and ability to produce functional immune cells. That gives us a scalable starting point to design 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 enter tumors, consume cancer cells, and help orchestrate immune responses. While T cell therapies have achieved great success against blood cancers, macrophage-based therapies may offer particular advantages against solid tumors.
However, mature macrophages have several drawbacks as therapeutic products. They are difficult to grow in large quantities outside the body, are difficult to genetically modify, and can be damaged during freezing and storage. They also tend 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 his colleagues in the Ying Laboratory focused on GMPs, which are at an earlier stage in the developmental pathway that produces macrophages.
Using a carefully defined chemical cocktail, the team prevented GMP from maturing into other types of immune cells and managed to maintain and expand them for long periods in the laboratory.
Even after prolonged growth, the cells retained their molecular and cellular characteristics and continued to generate functional macrophages and other immune cells.
Researchers in the laboratory of Ravi Majeti, MD, PhD, at Stanford University, independently reproduced the long-term maintenance and genetic engineering of GMPs, providing additional support for the reliability of the platform and its potential therapeutic value.
Majeti, director of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University, said: “This approach to expanding and engineering GMP opens the door to numerous translational applications, much like expanding and engineering T cells. We have already demonstrated the engineering of these cells to drive multiple powerful functions, and there is much more to explore.”
GMP engineering to fight cancer
Beyond their ability to grow long-term in the laboratory, GMPs can also be genetically modified for use as immunotherapies.
In this study, the researchers equipped GMP with a chimeric antigen receptor, or CAR, which allows cells to recognize a specific marker found on cancer cells. The team also added a second signal designed to activate nearby immune cells that help stimulate tumor-fighting T cells and strengthen the body’s natural defenses.
Importantly, this additional signal remains effective even when the donor and recipient cells are immunologically mismatched. That raises the possibility of creating off-the-shelf therapies produced in advance from donor cells and used in many patients, rather than generating a personalized treatment for each individual.
After scaling up and engineering both mouse and human GMPs, the researchers tested them in mice. The cells successfully settled in the bone marrow and other blood-forming tissues, where they continuously generated engineered macrophages and additional immune cells.
Because GMPs maintained a continuous supply of these cells from the bone marrow, they avoided the rapid loss that has limited mature macrophage therapies, including those evaluated in recent clinical trials.
In mice with blood cancers and solid tumors, CAR-engineered GMP slowed disease progression. GMPs carrying both the CAR and the additional immune activation signal produced even greater benefits.
Potential beyond cancer
The platform may have applications beyond oncology.
The researchers tested the method in mice with chronic granulomatous disease, an inherited immune disorder. The GMP treatment restored the animals’ ability to fight bacterial infections, also demonstrating the technology’s potential for immune deficiencies.
“Our study suggests that the future of immunotherapy may depend not only on designing better CAR receptors, but also on choosing the right stage of cell development,” Ying said.
About the study
the role in Cell is titled “CAR Expansion and Engineering of Granulocyte-Monocyte Progenitors for Cellular Immunotherapy.”
In addition to Ying, Yue, and Majeti, other authors 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 of USC; and 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 Dana-Farber Cancer Institute.
This work was supported by the Chen Yong Foundation of the Zhongmei Group, a research project sponsored by Myelogene Inc., the LK Whittier Foundation, the Eli and Edythe Broad Innovation Award, the Ming Hsieh Institute for Cancer Engineering Medicine Research Award, the USC SBIR/STTR Planning Award, the Xia Research Fund, and the Wu & Jiang Research Fund. Majeti reports support from the Ludwig Institute for Cancer Research, and Guo was supported by the California Institute for Regenerative Medicine predoctoral training fellowship.
Disclosures
Ying, Yue, Jing, Guo, Majeti, Zhang, Nguyen, and Tang are co-inventors on patents related to this study, filed by USC and licensed to Myelogene Inc. Ying, Yue, Zhang, and Majeti are co-founders of Myelogene Inc. Majeti serves on the advisory boards of Kodikaz Therapeutic Solutions, Pheast Therapeutics, Prelude Therapeutics, Mubadala Capital, Aculeus Therapeutics, Sequentify, BMS and Bectas Therapeutics. Majeti is also a co-founder and shareholder of Pheast Therapeutics.