Next-Generation CAR-T Cell Immunotherapies for Pediatric Acute Myeloid Leukemia
In recent years, researchers have found ways to artificially reprogram our own immune system so that it recognizes specific markers and fights tumor cells. Unfortunately, certain pediatric cancers, such as acute myeloid leukemia (a type of blood cancer), are difficult to treat because the cells that make up the tumor either have the same targets as healthy cells, causing undesired effects on normal organs, or are resistant to elimination by the immune system. We recently published a method to solve the first issue, which involves making normal bone marrow cells ‘invisible’ to the immune therapy, so that they are not eliminated and continue to form blood cells. This approach allows potent immunotherapy without adverse effects, which would otherwise preclude the use of life-saving treatments in children. Despite the success of this strategy, several other cancers, including non-hematological tumors, are poorly responsive to engineered immune cells. We now want to find a solution to this second issue, this time by making the immune cells more capable of eliminating tumors by giving them diverse and more effective ways to kill. We hope that by optimizing the way in which T lymphocytes kill cancer cells, we can successfully eliminate resistant tumors and stimulate an enduring response preventing relapse. Critically, we believe that the discoveries deriving from this project will be fundamental to develop the next generation of immune therapies for several pediatric cancers.
Project Goal:
Acute Myeloid Leukemia (AML) in children is a devastating cancer with limited treatment options. This research seeks to overcome major hurdles preventing safe and effective use of CAR-T cell immunotherapy—a revolutionary approach where a patient’s immune cells are engineered to fight cancer. Although CAR-T cells have shown success in other blood cancers, AML presents unique challenges. Three main challenges remain: (1) CAR-T cells struggle to effectively kill AML cells, unlike in other cancers; (2) modifying blood stem cells, which sustain blood production for life, requires extreme precision to prevent long-term risks; and (3) CAR-T treatments can inadvertently harm bone marrow function through inflammatory side effects. To address these challenges, we propose three aims. 1) Boost CAR-T efficacy. By equipping CAR-T cells with advanced killing mechanisms, we aim to overcome cancer cell resistance and improve their effectiveness across multiple cancers. 2) Develop safer genome-editing tools. Using cutting-edge "base editing" technology, we will refine how genes are precisely edited to avoid unintended changes and improve safety. 3) Reduce side effects. We will engineer CAR-T cells to minimize inflammation that damages bone marrow, while maintaining their cancer-fighting abilities. Focusing on pediatric AML as a model, this research holds potential to transform CAR-T therapies for childhood cancers and beyond, improving both safety and effectiveness.
