Patients with relapsed blood cancers after allogeneic stem cell transplant are often treated with donor lymphocyte infusion (DLI), a type of immunotherapy that boosts the anti-tumor response and aims to induce cancer remission. The success of DLI varies from patient to patient. Dr. Bachireddy aims to investigate the determinants of DLI success and failure by studying the leukemic and immune cells during response to immunotherapy. Careful study of successful anti-tumor immune responses may reveal insights into tumor-immune interactions that may be relevant to predicting patient response to novel immunotherapies in other tumors.

Dr. Brown studies acute lymphoblastic leukemia (ALL), an aggressive leukemia and one of the most common malignancies in children and adolescents. Despite significant progress, relapse is associated with high rates of drug resistance and poor prognosis. As a result, relapsed ALL is the leading cause of cancer-related death in children. Dr. Brown will use large-scale genetic (DNA) and transcriptomic (RNA) data and leukemia animal models to dissect how a small number of ALL cells are able to escape the cytotoxic effects of chemotherapy. These cells then undergo genetic and epigenetic changes that allow them to generate resistance to chemotherapy and proliferate, causing relapse of this devastating childhood disease. Understanding this process may lead to novel therapeutic approaches for relapsed ALL.

Cutaneous T cell lymphoma (CTCL) is an incurable cancer of the immune T cells in the skin. In advanced disease, the cells escape into the blood, the lymph nodes, and at times the visceral organs. Patients with advanced disease eventually succumb to a combination of tumor burden and disease-related immunosuppression. Dr. Choi [Doris Duke-Damon Runyon Clinical Investigator] has recently used next generation sequencing to identify gene mutations that he hypothesizes are important for CTCL pathogenesis. He will molecularly dissect how these gene mutations alter signaling pathways in CTCL, using human models and patient samples. His ultimate goal is to identify novel therapeutic strategies that selectively target CTCL cancer cells, hastening the development of a cure for this intractable disease.

Dr. Daniels aims to improve the ability of engineered T cells to kill cancer. Specifically, his goal is to understand how signaling events during T cell activation determine the therapeutic properties of activated T cells. He uses synthetic immunology techniques and computational methods to search for synthetic receptors that confer desired functions upon T cells. Ultimately, he hopes to design and create receptors that improve the ability of T cells to proliferate, persist, recruit other immune cells, and kill cancer cells.

The human gut is home to trillions of microorganisms, collectively called the microbiota, which affect health and disease. For example, in patients receiving hematopoietic stem cell transplantation as treatment for leukemias, lymphomas and other blood cancers, disruptions in the microbiota have been linked to disease relapse, infections and reduced survival. To address these treatment complications, Drs. David and Sung are developing ways to manipulate the microbiota through prebiotics, carbohydrates that a patient can ingest to stimulate the growth and maintenance of various beneficial bacteria. The challenge is that each patient has different microbiota and therefore may respond differently to the same prebiotic therapy. They are developing approaches for personalizing prebiotic treatments for hematopoietic stem cell transplant (HCT) patients based on their individual gut microbiota. After validating their prebiotic personalization with a mouse model, they will test the safety and feasibility of this treatment in a Phase 1 clinical trial with HCT patients.

Dr. Didychuk is investigating the mechanism by which the Kaposi’s sarcoma herpesvirus (KSHV) co-opts the cellular host machinery to produce its own gene products in a manner distinct from other viruses and host cells. This research should reveal insights into this unique mode of transcriptional control. KHSV is an oncogenic virus that causes various cancers including, Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease, in immunocompromised individuals.

Leukemia is, for some patients, an inherited disease that may affect multiple individuals within a single family. Similar to other diseases such as inherited breast cancer, we now understand that specific genes may increase an individual's risk for developing leukemia over the course of his or her lifetime. While an increasing number of genes involved in inherited leukemia have been identified, the underlying molecular mechanisms that contribute to the development of leukemia and other blood cancers are less well understood. Some individuals with inherited blood cancers develop abnormal blood conditions years before actually developing overt leukemia. Dr. Drazer aims to better understand the molecular mechanisms that cause these abnormal blood conditions to transition into leukemia. The goal of this work is to apply these findings to inform future therapies for patients with blood cancers.

Mutations in the cancer-causing oncogene JAK2 are a hallmark of myeloproliferative neoplasms (MPNs), a blood disorder characterized by over-production of mature blood cells. While currently available JAK2 inhibitors improve symptoms, they are unsuccessful at completely eradicating diseased cells, so remissions are rare. Using genetically engineered mice, Dr. Dunbar will investigate how MPN cells remain dependent on JAK2 signaling for cell growth, and how additional mutations in the epigenome (the proteins involved in regulating gene expression) might contribute to drug resistance. His research aims to identify improved JAK2 inhibitors and lend insight into whether targeting both oncogenic drivers and epigenetic defects could be required for effective therapy. Ultimately, he hopes these findings will translate into better treatments for patients with these cancers.

Christopher’s research centers on the earliest steps whereby normal cells transform into abnormal cells with the potential to become cancer. He will focus on better understanding the first steps of the process by which normal blood cells become lymphomas, cancers that are generally thought to arise from blood cells that have already committed to becoming lymphocytes, an important component of the immune system. He hypothesizes, however, that some lymphomas actually arise from earlier hematopoietic stem cells (HSCs). He will interrogate this hypothesis by studying a cohort of lymphoma patients who also have detectable genetic mutations in HSCs that are known to be associated with blood cancers – a condition known as clonal hematopoiesis of indeterminate potential, or CHIP – to determine whether the mutations in the HSCs were the earliest events in the development of the patients’ lymphomas. Having a better understanding of lymphomas’ cellular basis will hopefully allow new insights into their clinical behavior and therapeutic vulnerabilities.

New drugs that target metabolic pathways have shown promise for the treatment of cancer, but the benefits of these drugs have been restricted to rare patients whose cancers have mutations in specific metabolic enzymes. Dr. Intlekofer identified a metabolic pathway whereby subpopulations of genetically identical cancer cells produce a metabolite called L-2-hydroxyglutarate (L-2HG) that induces stem cell-like properties associated with resistance to anti-cancer therapies. He is investigating the mechanisms by which L-2HG regulates the identity and function of cancer stem cells in order to determine whether targeting the L-2HG pathway represents a broadly applicable strategy for treating cancer.