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

Year Awarded:

2021

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.

Co-funded by:

Northwestern Mutual Foundation

Alex's Lemonade Stand Foundation for Childhood Cancer

Childhood Cancer