Project Term
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Project Summary
Mutations in the RNA splicing factor gene SRSF2 occur in 25% of patients with MDS, 50% of patients with chronic myelomonocytic leukemia (CMML), and 25% of AML patients over the age of 65. We recently developed a cell therapy directed against abnormal proteins on the surface of cells expressing mutant SRSF2. This proposal aims to improve this new form of immunotherapy and extend its benefit to the largest number of patients with myeloid blood cancers.
Lay Abstract
Myeloid leukemias including myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML) are blood cancers most common in adults over 65 years old. Despite recent therapeutic advances, most adults with myeloid leukemias have disease that does not respond to treatment or are not healthy enough to receive curative therapy. As a result, only ~38% of adults with MDS, ~30% of adults with AML, and ~10-20% of adults with CMML survive beyond 5 years after diagnosis. These statistics highlight the urgent need for the discovery of new treatments for these diseases.
Immunotherapies, including antibody and T cell directed therapy, help the patient’s own immune system fight cancer. These therapies have been shown to be highly effective and well-tolerated in a variety of cancers. Unfortunately, currently available immunotherapies have been ineffective in patients with myeloid leukemias.
In this proposal, we aim to discover new and effective immunotherapy targets for the treatment of myeloid leukemias. One major challenge with immunologic therapies in myeloid leukemias has been the lack of targets, also known as “neoantigens”, that are specific for the blood cancer and are not found on normal non-cancerous cells. We have previously shown that mutations in genes involved in the cellular process of RNA splicing result in generation of new and previously unknown neoantigens. Discovering what these neoantigens are and how they interact with the immune system is extremely important in order to develop novel immunotherapies for myeloid leukemias.
We have focused our proposal on uncovering neoantigens generated in patients with myeloid leukemias that have mutations in the RNA splicing factor SRSF2. These mutations are found in a high percentage of patients with myeloid leukemias. We have already identified a group of neoantigens that are uniquely expressed in SRSF2 mutated leukemia cells and a corresponding panel of T cell receptors (TCRs) specifically identifying these neoantigens. Moreover, we have found that genetically modifying T cells with these TCRs result in selective elimination of SRSF2 mutant cells.
Our proposal is unique because we will identify new targets specific to cancer cells as well as the immune cells that recognize these targets. Targeting neoantigens specifically expressed on cancer cells will greatly reduce side effects as these proteins are totally unique to tumor cells. We anticipate that our work will lead to the development of novel immunotherapies for myeloid leukemias and could improve the lives of patients with these diseases.
Program
