Activating Anti-MDS Immunity Through Restoration of the Immune Microenvironment
Abstract
Myelodysplastic syndrome (MDS) is a disease of old stem cells characterized by poor bone marrow maturation and failure of normal blood cell production. The most active drugs against MDS (azacitidine and decitabine) are DNA hypomethylating agents (HMAs). These drugs improve blood cell production and quality of life for about half of treated patients, but responses are transient, and we cannot predict who will benefit before treatment starts. There is excitement about immune activating treatments (Immunotherapies) for patients with MDS. Such treatments can work for melanomas, lung cancers, and kidney cancers. Research has now shown that responses depend upon immune activating cells called dendritic cells (DCs). DCs eat up dead and dying cells and use this material to educate T-cells, which then target and kill cancers. In patients with solid tumors, infiltration of tumors by DCs that express a protein called CD141 (CD141^Hi DCs) is associated with better overall survival. This DC population is especially good at educating T-cells to kill off cancer. Unfortunately, MDS patients make less DCs of this type. Moreover, MDS patients with the lowest numbers of DCs had the shortest survival. Based on this finding, we think that restoring the function of CD141^Hi DCs in patients with MDS will help the immune system to educate T-cells and kill MDS cancer cells. This population might be important for the activity of HMAs, and to the efficacy of new immunotherapy treatments for people with MDS. This idea will address the Focus Area of finding effective BMF treatments and cures. To test this idea, we will perform a series of experiments using blood and bone marrow samples from patients and animal models of MDS to address two major research questions: (1) Can we generate functional DCs that can educate T-cells from the blood and bone marrow of MDS patients? and (2) Can we administer these DCs as a vaccine in combination with an HMA to improve survival in an MDS model? To answer the first question, we will use a method for growing DCs in a dish. This method has already been used to grow DCs from patients with other types of cancer. These DCs are safe to give to patients and thus, our results can be rapidly offered to patients. To answer the second question, we will generate mouse DCs using a similar technique and then inject them into mice with MDS to test how these DCs educate the immune system to kill MDS blasts. Studies of these important immune cells and how they can be developed into new treatments have never been done in MDS. We believe that a better understanding of the biology of DCs in patients with MDS and their use as therapy can help to improve quality of life and survival in patients with MDS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211072
Entities
People
- Michael Nemeth
Organizations
- United States Army