Activating Metabolic Pathways to Increase the Persistence of Leukemia Targeting T Cells
Institution:
Children’s Hospital of Pittsburgh
Researcher(s):
Erica Braverman, MD
Grant Type:
Young Investigator Grants
Type of Childhood Cancer:
Leukemia, Acute Lymphoblastic Leukemia (ALL)
Project Description:
The treatment of pediatric cancer requires the use of chemotherapy drugs, which carry a variety of long-term health consequences and are not always successful. New and exciting cancer treatments, known as immunotherapy, are looking to change this by using a patient’s own immune system to fight their cancer. These treatments have the potential to not only be more effective at curing cancer than traditional chemotherapy, but can also achieve a cure without the long-term consequences of chemotherapy. This is especially important in pediatric cancer treatment, where patients have a long life to lead after they are cured. One type of immunotherapy treatment, known as CAR-T cell therapy, has been used in pediatric leukemia with success, although over 1/3 of patients who initially respond to the therapy eventually relapse. CAR-T cell therapy has not been successful in other pediatric cancers, including sarcomas and lymphomas. In studying CAR-T cells, it has become clear that their metabolism, meaning the way in which they use nutrients as fuel to generate energy, significantly impacts their ability to kill cancer cells and remain long-term to prevent relapses. Therefore, uncovering ways to control the metabolic decisions of T cells would go a long way towards improving immunotherapy treatments in pediatric cancers.
Project Goal:
The goal of this grant is to find ways to improve the ability of CAR-T cells to kill cancer cells. In this way, we can improve the relapse rate after CAR-T therapy in pediatric leukemia and make CAR-T cell therapy available in other pediatric cancers. We will accomplish this by studying methods to control the way T cells burn energy, and using this information to make CAR-T cells better at destroying cancer cells and remaining long-term to prevent cancer relapse. Research in this area has shown the best way for T cells to use fuel in order to make them better at killing their targets. We have discovered a way to make T cells use their energy in this more effective way – we will now bring this method to CAR-T cells and test their ability to destroy cancer cells in mice. We will also use our knowledge to identify other methods to enforce this metabolic choice in T cells, increasing our ability to control T cells and therefore use them in these therapies more safely. This will make immunotherapy a viable option to cure pediatric cancers.
Project Update 2024:
The goal of this grant was to develop methods to improve the ability of CAR-T cells to kill cancer cells. This will help manage the relapse rate after CAR-T therapy in pediatric leukemia and make CAR-T cell therapy available in treating other pediatric cancers. We have set out to improve CAR-T cells in two ways – either by genetic manipulation or by drug treatment. At this point, we have generated exciting pre-clinical data using the drug treatment, which only requires that we treat the CAR-T cells while they are outside the patient. This will accelerate our ability to bring this to the clinic, since the treatment will not be given to the patient themselves. We are in the process of discussing this treatment with the FDA to potentially move towards clinical trials. In addition, our work in the genetically modified CAR-T cells has continued to advance. With new patient data demonstrating the qualities of CAR-T cells that are needed to permit long-lasting cures, we have now been able to demonstrate that our genetically modified CAR-T cells are able to acquire these characteristics better than standard CAR-T cells. We are now in the process of testing them in mouse models to generate the data needed to also move them into clinical trials. Finally, we have created another genetically modified CAR-T cell model which takes away the gene we are studying, and have been able to show that this gene is particularly important for CAR-T cell function. We will continue to use these models to better understand how this gene works so that we can use that knowledge to further improve CAR-T cells for both leukemia as well as other tumors.
Co-funded by:
Northwestern Mutual Foundation
