The myelodysplastic syndromes (MDS) are a group of clonal neoplastic hematologic disorders characterized by varying degrees of bone marrow failure, abnormal hematopoiesis, and proliferation of myeloid blast cells. Impaired maturation of hematopoietic progenitors is manifest clinically by peripheral cytopenias and morphologic abnormalities in the marrow (“dysplasia”). Thought to be disorders of hematopoietic stem cells, clonal cytogenetic abnormalities are frequently identified. Although the disease can evolve toward acute leukemia, morbidity and mortality most frequently result from a marrow failure syndrome.
Evidence exists that immune activation against hematopoietic elements frequently occurs in MDS patients, based on the identification of lymphocytic infiltrates in the marrow, oligoclonal expansion of T cells, and excessive production of tumor necrosis factor alpha. Whether this represents a secondary event in response to cell injury and the generation of neo-antigens, or an initiating event inducing immunopathology, remains controversial. Nevertheless, MDS are thought to be immunologically responsive diseases, as immunomodulatory drugs can induce remissions, and allogeneic bone marrow transplantation can be curative in the small fraction of patients for whom this is an option.
Recently, three classes of therapeutic agents have been shown to have activity in MDS; a) DNA methyltransferase inhibitors, b) histone deacetylase inhibitors (HDACi), and c) immunomodulatory derivatives (IMiDs) of thalidomide. Central to this proposal is the observation that all three classes of drugs augment discrete elements of host immunity, making their integration with therapeutic cancer vaccines ripe for exploration.
We have developed a genetically modified tumor cell vaccine for the treatment of myeloid malignancies. The human erythroleukemia cell line K562 has been stably transfected to secrete GM-CSF. K562 cells express many of the antigens shown to be overexpressed in myeloid leukemias and MDS. In early phase clinical trials for both acute and chronic myeloid leukemias, we have observed the induction of anti-tumor immunity and associated clinical responses following K562/GM-CSF vaccination (see preliminary data). In this proposal, we seek to evaluate the integration of K562/GM-CSF vaccination with systemic therapies for MDS that alter host immunity and/or hematopoietic cellular differentiation. Specifically, we will:
1. Examine the in vivo effect of: a) DNA methyltransferase inhibitors, b) HDACi, and c) IMiDs on the response to GM-CSF tumor vaccines in a mouse model (year 1).
2. Conduct a clinical trial in MDS testing K562/GM-CSF vaccination integrated with the systemic agent(s) identified in aim 1 as being most active in combination with GM-CSF tumor vaccines (years 2 and 3).
3. Evaluate immune responses specific for autologous MDS cells as well for as candidate antigens overexpressed in MDS using pre and post vaccination blood and marrow samples (years