Overview - Jacalyn Rosenblatt, M.D., is Head of the Multiple Myeloma Program and Co-Dirtector of the Cancer Vaccine Program within the Hematological Malignancy section at Beth Israel Deaconess Medical Center (BIDMC). She is an associate professor of medicine at Harvard Medical School.
Dr. Rosenblatt received her M.D. at McGill University School of Medicine. She received her internal medicine and residency training at McGill University Medical Center. She then was a clinical and research fellow in hematology/oncology at Beth Israel Deaconess Medical Center, Harvard Medical School. She received a Masters in Medical Science from Harvard Medical School. Dr. Rosenblatt joined the attending physician staff of hematology/oncology at BIDMC in 2003.
Dr. Rosenblatt's work has focused on designing immune based therapy for hematological malignancies, including AML. She has contributed to the development of a personalized tumor vaccine in which patient-derived tumor cells are fused with potent immune stimulating cells known as dendritic cells, to create a broad anti-tumor immune response. In a clinical study, vaccination of AML patients who achieved chemotherapy induced remission resulted in the expansion of AML specific T cells in the peripheral blood and bone marrow, and promising clinical outcomes.
In this project, strategies to enhance response to DC/AML fusion cell vaccination will be assessed. A potential concern is that leukemia initiating cells may evade T cell immunity through ineffective antigen presentation, the upregulation of PDL1, and recruitment of MDSCs that support tolerance in the bone marrow microenvironment facilitating escape. We have demonstrated that hypomethylating agents (HMA) enhance antigen presentation by AML cells and leukemic stem cells. We have also demonstrated that MUC1 plays a critical role in supporting immune escape by increasing AML expression of PDL1 and facilitating recruitment of MDSCs. As such, there is strong rationale for combining these HMA and agents that interfere with MUC1 signaling with the DC/AML fusion vaccine. In this project, the ability of HMA and MUC1 inhibition to enhance the immunogenicity of leukemic blasts and potentiate the efficacy of the DC/AML fusion vaccine will be examined in pre-clinical studies. The goal will be to translate these findings to a clinical trail to evaluate the combination of immunomodulatory agents with DC/AML fusion vaccine.
Dr. Raffel is currently an Associate Professor of Medicine in the Division of Hematology/Oncology at UMass Medical School. His laboratory focuses on identifying critical pathways necessary for early blood development and how they become co-opted during the process of leukemia formation. Dr. Raffel is also an Attending Physician at UMass Memorial Health Care where he is a member of the Bone Marrow Transplant/Hematologic Malignancy Service.
Lay Description: Today’s treatment of leukemia uses drugs which have extremely toxic side effects, therefore, it is crucial to search for new types of therapies that directly target leukemia without harming the normal cells of the body. A gene called MPL, makes a protein important for the growth and survival of a significant proportion of Acute Myeloid Leukemia (AMLs. Our laboratory has been focusing on the function of a variant of MPL produced by alternative splicing of the MPL RNA message used to make the protein. This variant, MPL-TR, opposes the function of MPL in cells and therefore we believe increasing its expression in leukemia cells will suppress their growth.
Anti-sense Oligonucleotides (AONs) are very short segments of RNA or DNA that can bind specifically to RNA messages in the cell, so no other genes are affected. By targeting AONs to the regions in MPL RNA important for splicing, we propose to cause the leukemia cells to make more MPL-TR and inhibit their growth and survival. We will test different chemical formats shown to increase AON binding, uptake and stability on human leukemia cell lines as well as samples directly from patients to evaluate their ability to interfere with MPL function and inhibit growth. Effective AONs will be tested on mice which have been transplanted with human leukemia cells to determine their effectiveness at preventing leukemia growth and demonstrating their potential as a new drug.