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Researchers at the University of California, Los Angeles (UCLA) have become the first to successfully develop mature, cancer-killing T cells in a laboratory setting.
The immune system's T cells fight infections; they also have the ability to fight cancer. Therapies that involve genetically engineering a patient's own T cells with a receptor that helps the T cells to recognize and destroy cancer cells have tremendous potential for certain types of cancer. One of these therapies is CAR T-cell therapy, which is used for patients with some forms of refractory non-Hodgkin lymphoma and young patients (under 25) with relapsed or refractory acute lymphoblastic leukemia. However, engineered T cells are not always effective, and some cancer patients cannot afford the high cost of the individually tailored treatment; others do not have enough T cells to make the treatment possible.
In a study published in Cell Stem Cell, the UCLA researchers have found a way to generate T cells from pluripotent stem cells, which are capable of developing into any cell type in the body and can be grown easily in a laboratory setting. The investigators achieved this feat using artificial thymic organoids. These continuous 3D organoid systems emulate the environment of the thymus, the bodily organ in which T cells emerge from blood stem cells.
Previously, other researchers had partially succeeded in producing T cells from pluripotent stem cells on a layer of supporting cells, but those T cells did not mature to become fully functional.
"The 3D structure of the artificial thymic organoid seems to provide the right supportive signals and environment needed for mature T cells to properly develop," commented the study's senior author, Gay Crooks, MBBS, Professor of Pathology and Laboratory Medicine and of Pediatrics and Co-Director of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.
"What's exciting is the fact that we start with pluripotent stem cells," she remarked. "My hope for the future of this technique is that we can combine it with the use of gene editing tools to create 'off-the-shelf' T-cell therapies that are more readily available for patients."
The researchers' method produced naive, antigen-specific CD8αβ+ T cells that lacked endogenous T-cell receptor (TCR) expression and were effective at fighting tumor cells, both in cell cultures and in mice.
"Once we create genetically edited pluripotent stem cell lines that can produce tumor-specific T cells in artificial thymic organoids, we can expand those stem cell lines indefinitely," said Amélie Montel-Hagen, PhD, one of the study's co-first authors and an Associate Project Scientist in Crooks's lab. The ability to expand these cell lines indefinitely could mean an indefinite supply of T cells for use in cancer treatments.
What needs to be done for this exciting development to make the leap from the lab to patient care?
"Our next step will be to create T cells that have the receptors to fight cancer but do not have the molecules that cause the rejection of the cells, which would be a major step toward the development of universal T-cell therapies," stated co-first author Christopher Seet, MD, PhD, a Clinical Instructor in the Division of Hematology-Oncology at UCLA.
For More Information
Montel-Hagen A, Seet CS, Li S, et al (2019). Organoid-induced differentiation of conventional T cells from human pluripotent stem cells. Cell Stem Cell. [Epub ahead of print] DOI:10.1016/j.stem.2018.12.011
Image credit: UCLA Broad Stem Cell Research Center