UCLA scientists have developed a unique technology for the differentiation of induced pluripotent stem cells (iPSCs) into mature T lymphocytes capable of killing tumor cells.
The method is based on the use of artificially created thymus organoid as an imitation of the natural environment for the development of T lymphocytes from hematopoietic stem cells.
T lymphocytes (T cells) are cells of the immune system that fight infections but also have the potential to eliminate cancer cells. The possibility of creating them from self-renewing iPSCs using the UCLA scientists’ methodology will help create new approaches in cancer immunotherapy and, possibly, stimulate further research on T cell therapy of viral infections such as HIV, and autoimmune diseases.
Among the most promising aspects of this method, is that it can be combined with gene editing technology to create virtually unlimited supply of T lymphocytes that can be used by a large number of patients, without the need to use their own T cells.
The study, which was published on January 17, 2019 in the journal Cell Stem Cell, was led by senior author Dr. Gay Crooks a 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.
T cell therapy, including CAR T cell therapy has shown great promise in the treatment of certain types of cancer. Modern methods consist of several stages: the collection of T cells from the patient; genetically engineering the T cells with a receptor that helps them recognize and kill cancer cells; and then cell transplantation back into the patient.
However, such T lymphocytes do not always function properly, treatment is quite expensive, because it is adapted individually for each patient, and in some cancer patients don’t have enough T cells to undergo such a course of treatment.
Therefore, a method that will allow the production of T lymphocytes without the need to obtain them from patients is an important step towards the creation of a more accessible and effective T cell therapy technique.
“What’s exciting is the fact that we start with pluripotent stem cells“, – Crooks said. “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.”
Other research groups have achieved only partial success in trying to create T lymphocytes using methods that include co-cultivating iPSCs with a layer of supporting cells. However, the T cells obtained in those previous studies did not mature to fully functional T lymphocytes.
Crooks and her team have previously demonstrated that the three-dimensional structure of the artificial thymus organoid allows mature T cells to grow from adult blood stem cells. They suggested that it would also work to create mature T cells from iPSCs.
“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 said.
Two different sources of pluripotent stem cells were used: obtained from embryos donated for research and created by reprogramming adult skin or blood cells into embryonic state. The experiment demonstrated that T lymphocytes obtained from both sources are equally effective in maturing in the thymus organoid.
The researchers also showed that they could genetically engineering pluripotent stem cells for expression of the receptor T cells target the cancer. And also, using thymus organoids, to create T lymphocytes, capable of detecting and killing tumor cells 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, the study’s first co-author and an associate project scientist in Crooks’ lab.
An unlimited supply of T lymphocytes capable of fighting various types of tumors will be an important turning point for cancer treatment.