Pluripotent Stem Cell-derived CAR-T and CAR-NK Cells for Immunotherapy of Leukemia and Lymphoma
George Daley
MD, PhDBoston Children's Hospital
Project Term: July 1, 2024 - June 30, 2027
Cytotoxic cells of the immune system, including T and NK cells, can be targeted to seek out and destroy leukemia, lymphoma and myeloma cells by engineering them to express chimeric antigen receptors (CARs) which empower the cell to home to and kill the cancer cells. Typically, such CAR-T and CAR-NK cells are generated from a patient's own blood, but sometimes heavy pre-treatment with chemotherapy leaves inadequate supplies of T and NK cells. We propose to generate T and NK cells from Pluripotent Stem Cells, which through genetic manipulation can be rendered suitable for treating any patient with an "off-the-shelf" cell product, hence facilitating otherwise cumbersome, labor-intensive, and expensive patient-specific cell therapies.
Cancer immunotherapy employing T and NK cells of the immune system, modified with tumor-targeting chimeric antigen receptors (CAR), has demonstrated remarkable efficacy against lymphoid leukemia and lymphoma. Nevertheless, their broader application has been hindered by the laborious patient-specific procedures for harvesting and engineering blood cells when patients are often heavily pre-treated and have low blood counts. Human induced pluripotent stem cells (iPSCs), which grow as immortal cells in tissue culture, present an attractive resource for scalable, “off-the-shelf” cell therapy manufacturing. However, the challenge lies in generating functionally mature T and NK cells from iPSCs, which because of their primitive embryonic nature tend to produce immature cell products that lack the robust efficacy of adult cells harvested from a patient’s blood. We have identified molecular pathways that guide development of immune cells, and discovered small drug-like molecules and genetic therapies that allow us to isolate functionally robust immune cells that closely mimic their counterparts from adult blood. In our proposal, we aim to optimize genetic and chemical methods for producing highly effective cancer-fighting T and NK cells from pluripotent stem cell sources. We will test these cytotoxic cells in humanized mouse models of leukemia and lymphoma in anticipation of translation of novel cell therapies into the clinic.