A UCLA study is the first to demonstrate a technique for coaxing pluripotent stem cells — which can give rise to every cell type in the body and which can be grown indefinitely in the lab — into becoming mature T cells capable of killing tumor cells. The technique uses structures called artificial thymic organoids, which work by mimicking the environment of the thymus, the organ in which T cells develop from blood stem cells.
T cells are cells of the immune system that fight infections but also have the potential to eliminate cancer cells. The ability to create T cells from self-renewing pluripotent stem cells could lead to new approaches to cancer immunotherapy and spur further research on T-cell therapies for viral infections such as HIV and autoimmune diseases. Among the technique’s most promising aspects is that it can be combined with gene-editing approaches to create a virtually unlimited supply of T cells able to be used across large numbers of patients without the need to use a patient’s own T cells.
T-cell therapies, including chimeric antigen receptor T-cell therapy, have shown great promise for treating certain types of cancer. Current approaches involve collecting T cells from a patient, genetically engineering the T cells with a receptor that helps them recognize and destroy cancer cells and then infusing the cells back into the patient. But engineered T cells do not always function well, treatment is expensive because it is tailored to each patient and some people with cancer don’t have enough T cells to undergo the therapy.
Therefore, a technique that produces T cells without relying on collecting them from patients is an important step toward making T-cell therapies more accessible, affordable and effective. “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,” says Gay Crooks, MBBS, professor of pathology and laboratory medicine and of pediatrics, co-director of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA and director of the Cancer and Stem Cell Biology Program at the UCLA Jonsson Comprehensive Cancer Center.
Dr. Crooks and her team previously demonstrated that the 3D structure of an artificial thymic organoid allowed mature T cells to develop from adult blood stem cells and hypothesized that they would also support mature T-cell production from pluripotent stem cells. “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,” she says.
One of the remaining challenges for the UCLA scientists is that the T cells created using the artificial thymic organoids have additional molecules on their surface that are not matched to each individual patient. Those extra molecules could cause a patient’s body to reject the transplanted cells. “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,” says Christopher Seet, MD (FEL ’14), PhD ’18, clinical instructor in the UCLA Division of Hematology and Oncology.
— Mirabai Vogt-James
“Organoid-induced Differentiation of Conventional T Cells from Human Pluripotent Stem Cells,” Cell Stem Cell, January 17, 2019