Researchers at USC Stem Cell have introduced a novel method for generating a sustainable and expandable supply of immune cell precursors, which may enhance cancer immunotherapy and other medical treatments.
The findings, published in the journal Cell, concentrate on granulocyte-monocyte progenitors (GMPs), a kind of progenitor cell that can create macrophages and other immune cells. Macrophages are crucial for defending against infections and are increasingly being looked at as effective tools for cancer treatment.
The team discovered that GMPs can be significantly expanded in the lab and can also be genetically modified to target cancer cells while enhancing overall immune responses.
“This study outlines a scalable and adaptable GMP platform for cellular immunotherapy and proposes ideas with potentially wide-ranging impacts on both cancer immunotherapy and stem cell science,” commented Qi-Long Ying, MD, PhD, a professor of stem cell biology and regenerative medicine at USC.
A particularly noteworthy finding was about self-renewal, a feature typically linked to stem cells. Self-renewal allows cells to divide continuously while retaining their identity. Traditionally, progenitor cells have not been seen as having this capability over the long term.
“It’s been generally accepted that the ability for long-term self-renewal within the blood system primarily belongs to hematopoietic stem cells, able to generate any type of blood or immune cell,” noted Ying. “Our research shows that, under optimal conditions, GMPs can also self-renew, dividing extensively while maintaining their identity and capability to produce effective immune cells. This gives us a promising foundation for developing cell therapies targeting cancer and infectious diseases, and possibly other conditions too.”
Why Are Macrophage Precursors Important?
Macrophages are considered viable candidates for cancer immunotherapy because they naturally infiltrate tumors, consume cancer cells, and help coordinate immune responses. While T-cell therapies have shown remarkable success in treating blood cancers, macrophage-based therapies could have unique advantages when addressing solid tumors.
However, there are challenges associated with using mature macrophages as treatment; they are tough to produce in large quantities outside the body, complicated to genetically modify, and can degrade when stored. They also tend to collect in organs like the lungs and liver, rather than dispersing throughout the body.
To tackle these issues, lead author Shi Yue, MD, and the Ying Lab team concentrated on GMPs, which are situated earlier in the developmental sequence leading to macrophages.
By employing a carefully calibrated chemical mixture, they managed to prevent GMPs from maturing into other immune cell types and successfully maintained and expanded them over prolonged periods in a lab environment.
Even after prolonged growth, these cells retained their molecular and cellular characteristics and continued producing functional macrophages and other immune cells.
Researchers in Ravi Majeti’s lab at Stanford University were able to independently replicate the long-term maintenance and genetic modification of GMPs, lending further credibility to the platform’s reliability and therapeutic potential.
Majeti, Director of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford, remarked: “This technique for the expansion and engineering of GMPs paves the way for numerous translational applications, similar to T cell expansion and engineering. We’ve already shown that these cells can be engineered to drive multiple potent functions, and there’s still much to uncover.”
Engineering GMPs to Combat Cancer
In addition to their capacity for long-term growth in the lab, GMPs can also be genetically modified for immunotherapeutic use.
In this research, the team equipped GMPs with a chimeric antigen receptor (CAR), enabling them to identify a specific marker present on cancer cells. They also integrated a secondary signal intended to activate neighboring immune cells, which helps stimulate T cells that combat tumors and bolster the body’s natural defenses.
Significantly, this additional signal remains effective even when there’s an immunological mismatch between donor and recipient cells. This suggests the possibility of developing off-the-shelf therapies produced in advance from donor cells, usable by multiple patients rather than requiring individual custom treatments.
After expanding and engineering both mouse and human GMPs, the researchers tested them in mice. The cells were successful in settling into the bone marrow and other blood-producing tissues, where they consistently generated engineered macrophages and other immune cells.
Since the GMPs maintained a continual supply of these cells from the bone marrow, they avoided the rapid decline seen in mature macrophage therapies that have been tested in recent clinical trials.
In mice with blood cancers and solid tumors, CAR-engineered GMPs slowed disease progression. Notably, GMPs hosting both the CAR and the immune-activating signal showed even stronger effects.
Potential Applications Beyond Cancer
This platform might also have implications beyond cancer treatment.
The researchers evaluated the approach in mice suffering from chronic granulomatous disease, an inherited immune disorder. Treatment with GMPs restored the animals’ ability to combat bacterial infections, indicating the technology’s potential for addressing immune deficiencies as well.
“Our research suggests that the future of immunotherapy may rely not just on designing improved CAR receptors, but also on selecting the appropriate developmental stage of the cell,” Ying concluded.
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, additional contributors to the study 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 from USC; Litao Tao and Celia Bloom from Creighton University; Asiri Ediriwickrema and Sebastian Koschade from Stanford University School of Medicine; and Yingxiao Shi from Harvard Medical School and the Dana-Farber Cancer Institute.
This work received support from various organizations including the Chen Yong Foundation of the Zhongmei Group and the USC SBIR/STTR Planning Award, among others.
Disclosures
The co-inventors linked to this study, who hold patents filed by USC and licensed to Myelogene Inc., include Ying, Yue, Jing, Guo, Majeti, Zhang, Nguyen, and Tang. Ying, Yue, Zhang, and Majeti co-founded Myelogene Inc. Majeti serves on advisory boards for several therapeutic companies and is also a co-founder and equity holder of one of them.
