It is now well accepted that the immune system, or its dysregulation, plays a central role in causing or worsening many of the most common and life-threatening diseases, such as cancer, HIV1 infection, and autoimmune disorders like diabetes. Recent research has raised the exciting possibility that cells of the immune system might be engineered to treat disease. The immune system is produced from blood-forming stem and progenitor cells (Hematopoietic Progenitor Cells/HPC) and consists of different types of lymphoid cells; of these, T cells are essential for immune-competence. In laboratory research, T cells have been engineered to kill cancer cells, become resistant to infections like HIV-1 and produce immune tolerance for autoimmune disease. In many cases, the use of adult sources of HPC or T cells (bone marrow and blood) is not optimal or even feasible. For example, HPC and T cells are absent after bone marrow transplantation and deficient after chemotherapy, they may be infected as in the case of HIV-1, or contaminated with malignant cells as in leukemia. In addition, adult HPC and T cells do not self-renew during culture and so the ability to engineer or expand them to target disease is very limited. Blood cells can be produced from pluripotent stem cells (PSC), i.e. human embryonic stem cells (hESC) and reprogrammed adult cells aka “induced pluripotent stem cells” (iPSC). Our group has shown that PSC-derived HPC can produce T cells after transplantation in mice. This finding opens up unlimited theoretical opportunities for immune cell therapy that would use banks of iPSC, perfectly matched to each patient, that can be expanded in culture indefinitely and can be engineered to produce T cells that target specific diseases, for example to treat cancer, restore the immune system after bone marrow transplantation, chemotherapy and severe infection, and produce immune tolerance to suppress autoimmune diseases and prevent organ rejection after transplantation. However, PSC-derived immune therapy cannot be brought to clinical translation because of the following bottleneck: Current methods of differentiating PSC produce a very low yield of HPC, and these HPC are inefficient at generating the cells of the immune system. In addition, the culture methods are not clinically useful as they involve the co-culture of human PSC with mouse cells. Our goal is to develop methods that can be used clinically to efficiently produce HPC that can in turn generate the cells (particularly T cells) of the immune system. This proposal brings together a multidisciplinary team of physicians and scientists with expertise in the biology of hESC, iPSC, HPC, the development of the immune system, clinical cell therapy and transplantation. These advances will have direct and immediate application for medical therapies that regenerate and regulate the immune system and open therapeutic possibilities for many serious diseases.
Statement of Benefit to California:
Development of methods for regenerative medicine using stem cells will have wide-spread applications to improve the health of millions of Californians and to provide novel, effective therapies for tens of millions of people world-wide. One major area of clinical promise involves the production of blood forming (hematopoietic) progenitors from pluripotent stem cells (PSC) to regenerate and regulate the immune system. Many severe medical conditions can be cured or improved by transplantation of blood-forming hematopoietic stem and progenitor cells (HPC), including cancer and leukemia, genetic diseases of blood cells, such as sickle cell disease and inborn errors of metabolism or of the immune system. HPC may be engineered to make them resistant to infections (e.g. HIV/AIDS) or to target specific cancers and leukemias. Additionally, transplants of HPC may induce states of immunological tolerance to provide new treatments for auto-immune diseases (e.g. Diabetes, rheumatoid arthritis, systemic lupus erythematosis) and to prevent rejection of transplanted cells or organs (e.g. kidney, liver, heart, lung). A major bottleneck to the use of PSC as a source of immune cell therapy is the low numbers of HPC that currently can be made from PSC and the relative inability of these HPC to produce the lymphocytes (T, B and NK cells) that comprise the immune system. This proposal brings together experts in the biology of stem cells, the mechanisms for development of the immune system, and the methods used to interrogate and to manipulate these cell systems. A logical series of milestones will be achieved to improve production of HPC from PSC using methods that can be used clinically and to improve the ability of HPC, in turn, to produce the immune system, These advances will have direct and immediate application for medical therapies that regenerate and regulate the immune system and will thus have wide-ranging application to the many diseases now known to be caused or worsened by immune dysregulation. All scientific findings and biomedical materials produced from our studies will be publicly available to non-profit and academic organizations in California, and any intellectual property developed by this Project will be developed under the guidelines of CIRM to benefit the people of the State of California.