What the researchers found
Scientists at the University of Southern California have developed a way to produce what could be a renewable supply of cancer-fighting immune cells, according to a study published in Cell and summarized by Science Daily. The team worked with granulocyte-monocyte progenitors, or GMPs, which are immature cells that normally develop into macrophages and other immune cells.
The researchers reported that GMPs can be grown extensively in the laboratory while keeping their ability to become functioning immune cells. The cells can also be genetically modified to recognize specific cancer markers and to strengthen wider immune responses.
In experiments with mice, the engineered cells established themselves in bone marrow, produced new immune cells and slowed the progression of both blood cancers and solid tumors.
A challenge to a long-held view
The finding also bears on basic biology. Self-renewal, the ability to divide repeatedly while keeping original properties, has traditionally been tied mainly to hematopoietic stem cells, which can generate all major types of blood and immune cells. Progenitor cells are further along in development and are generally thought to have less capacity for long-term self-renewal.
The USC team showed that GMPs can self-renew under carefully controlled laboratory conditions. Qi-Long Ying, the study's corresponding author and a professor of stem cell biology and regenerative medicine at the Keck School of Medicine of USC, said: "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."
Why start with progenitors instead of macrophages
Macrophages, whose name comes from Greek words meaning "big eaters," engulf bacteria and damaged cells and help coordinate other immune cells. Some can enter tumors and attack cancer cells, which makes them attractive for treating solid tumors. Engineered T-cell therapies have had their greatest successes against certain blood cancers, while solid tumors have proved harder to treat.
Mature macrophages are difficult to multiply in large quantities outside the body and hard to modify genetically, and they can be damaged by freezing and storage. After infusion, they often collect in organs such as the lungs and liver rather than spreading widely, and they can disappear relatively quickly.
To get around these problems, first author Shi Yue and colleagues developed a precisely defined chemical mixture that let GMPs survive and multiply for extended periods while preventing them from maturing too early. After extensive expansion, the cells kept their defining molecular characteristics and could still become functional macrophages and related cells.
Engineering the cells and outside validation
The team engineered GMPs to carry a chimeric antigen receptor, or CAR, which lets immune cells identify a particular marker on cancer cells. CAR technology is already used in treatments that modify a patient's T cells. Some progenitor cells also received an additional immune-activating signal meant to recruit and stimulate nearby immune cells, including T cells.
To test reproducibility, collaborators in the Stanford University laboratory of Ravi Majeti independently showed that GMPs could be maintained for extended periods and genetically engineered. Majeti, who directs Stanford's Institute for Stem Cell Biology and Regenerative Medicine, said the method "opens the door to numerous translational applications, much like T cell expansion and engineering."
