By William A. Baruwa
Scientists at the University of Southern California (USC) have developed a promising new approach to cancer immunotherapy by discovering a way to produce a potentially renewable supply of genetically engineered immune cells capable of recognising and attacking cancer.
The breakthrough could address some of the major limitations of existing cell-based cancer treatments, particularly the difficulty of producing sufficient quantities of therapeutic immune cells and ensuring they remain active in the body for extended periods. The research, published in Cell, is titled “Expansion and CAR engineering of granulocyte-monocyte progenitors for cellular immunotherapy.”
The researchers developed a technique for growing and genetically modifying immature immune cells, enabling them to multiply extensively while retaining their ability to develop into specialised cancer-fighting cells.
In experiments involving mice, the engineered cells established themselves in the bone marrow, where they continued producing additional immune cells. The approach slowed the progression of both blood cancers and solid tumours, raising hopes for a new generation of potentially longer-lasting cancer treatments.
The findings, published in the journal Cell, could also pave the way for ready-made immunotherapies that can be manufactured in advance and made available to multiple patients, rather than requiring individual preparation for each person.
A New Approach to Engineering Cancer-Fighting Cells
The USC Stem Cell-led research team focused on a type of immature immune cell known as granulocyte-monocyte progenitors (GMPs).
These cells normally develop into macrophages and other immune cells that help protect the body against infections and participate in immune responses.
The scientists discovered that GMPs could be multiplied extensively under carefully controlled laboratory conditions without losing their ability to develop into functional immune cells. They also demonstrated that the cells could be genetically modified to recognise specific cancer markers and stimulate wider immune responses.
The study’s corresponding author, Qi-Long Ying, MD, PhD, professor of stem cell biology and regenerative medicine at the Keck School of Medicine of USC, described the discovery as an important development for cellular immunotherapy.
“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,” Ying said.
Challenging Established Understanding of Stem Cells
Beyond its potential implications for cancer treatment, the discovery challenges conventional scientific understanding of how blood and immune cells develop.
Stem cells are known for their ability to self-renew, repeatedly dividing while maintaining their original characteristics. In the blood-forming system, this capacity has traditionally been associated mainly with haematopoietic stem cells, which can generate the different types of blood and immune cells.
Progenitor cells, however, are generally considered to be further along the developmental process and have a more limited capacity for long-term self-renewal.
The USC researchers found that GMPs could also retain this ability under specific laboratory conditions. Instead of rapidly maturing into other cell types, the progenitors continued multiplying while preserving their identity and capacity to produce functional immune cells.
“The prevailing view has been that long-term self-renewal in the blood system is primarily a property of the haematopoietic stem cells that can generate any type of blood or immune cell,” Ying explained.
“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.”
To achieve this, the researchers developed a precisely formulated mixture of chemicals that enabled the GMPs to survive and multiply for extended periods in the laboratory without prematurely developing into mature immune cells.
Even after extensive multiplication, the cells retained their defining molecular characteristics and their ability to develop into functional macrophages and related immune cells.
The approach could therefore make it easier to manufacture large quantities of engineered immune cells from a renewable starting population, eliminating the need to repeatedly collect and prepare mature cells.
Researchers working with Ravi Majeti, MD, PhD, at Stanford University independently reproduced the technique, demonstrating that GMPs could be maintained for extended periods and genetically engineered.
Majeti, director of Stanford University’s Institute for Stem Cell Biology and Regenerative Medicine, said the development could open up several possibilities for future medical applications.
“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,” he said.
Programming Immune Cells to Recognise and Attack Cancer
Having established a method for expanding GMPs, the scientists investigated whether the cells could be genetically programmed to target cancer.
They equipped the progenitor cells with a chimeric antigen receptor (CAR), an engineered structure that enables immune cells to recognise specific molecular markers on cancer cells and direct their attack towards tumours.
CAR technology is already an important component of cancer immunotherapy, particularly in treatments involving genetically modified T cells.
The USC team explored whether a similar approach could be applied to GMPs, enabling them to generate engineered macrophages and other immune cells capable of targeting cancer.
The researchers went further by equipping some of the progenitor cells with an additional immune-activating signal designed to recruit and stimulate neighbouring immune cells, including T cells.
This modification was intended to produce a broader and potentially stronger immune response against cancer.
Significantly, the additional signal remained effective even when the immune characteristics of donor cells did not match those of the recipient.
The finding raises the possibility of developing so-called off-the-shelf treatments, in which engineered cells are manufactured in advance from donors, stored and made available for use by different patients.
This could represent an important departure from personalised cell therapies that require cells to be collected and modified separately for each patient.
Promising Results Against Blood and Solid Cancers
The researchers subsequently tested the engineered GMPs in mice to determine their ability to fight cancer.
Following administration, the progenitor cells established themselves in the bone marrow and other blood-producing locations, where they generated additional engineered macrophages and related immune cells.
Unlike treatments that depend entirely on mature macrophages, which may disappear relatively quickly, the new approach could provide a continuing supply of replacement immune cells from within the body.
The scientists tested the treatment in mice with blood cancers and solid tumours. In both cases, GMPs carrying CAR receptors slowed disease progression.
The results were even more encouraging when the engineered cells carried both CAR receptors and the additional immune-activating signal. This combination improved their ability to stimulate a wider antitumour response.
The researchers believe the approach could help overcome some of the limitations associated with existing macrophage-based therapies, including the rapid clearance of therapeutic cells from the body.
However, the findings remain at the preclinical stage. Further studies will be necessary to establish the safety, effectiveness and long-term behaviour of the engineered cells in humans.
Potential Benefits Beyond Cancer
The discovery may also have applications beyond cancer treatment, particularly in managing inherited disorders that weaken the immune system.
In a separate experiment, the researchers investigated whether engineered GMPs could help treat chronic granulomatous disease, an inherited condition that affects the ability of certain immune cells to destroy harmful microbes.
People living with the disorder are vulnerable to recurrent bacterial and fungal infections because their immune cells cannot effectively eliminate some disease-causing organisms.
When the researchers administered GMPs to mice with the condition, the engineered cells restored the animals’ ability to fight bacterial infections.
The result suggests that renewable populations of genetically modified immune cell progenitors could eventually be useful in treating inherited immune deficiencies and potentially other infectious diseases.
According to the researchers, the findings highlight the importance of selecting the appropriate developmental stage of immune cells when designing future immunotherapies.
By genetically modifying cells before they fully mature, scientists may be able to develop treatments that are easier to manufacture, more adaptable and capable of maintaining a continuing supply of specialised 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,” Ying said.
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