Myelodysplastic syndromes (MDS) are characterized by incompetent hematopoiesis that leads to single or multi-lineage peripheral cytopenias with the development of acute myeloid leukemia (AML) in approximately 30-40% of cases. The etiology of MDS is unknown and the factors leading to AML progression are not well characterized. With similarity to other cancer patients, MDS patients have defects in proximal T-cell receptor signaling pathways and altered T-cell homeostasis. A new class of interesting therapeutic drugs (IMiDs), derived from the parent compound thalidomide, has shown activity in a variety of inflammatory, autoimmune, and neoplastic diseases including MDS where clinical responses were observed and the drug was awarded FDA approval in select patients. Lenalidomide, as well as other IMiDs, possess a unique ability to augment T-cell function by substituting for inadequate secondary antigen-independent co-stimulatory signals through an unknown mechanism that involves activation of the CD28 receptor. Lenalidomide was able to reverse peripheral T-cell anergy, enhance TH1-type cytokine responses, and change T-cell homeostasis in patients with MDS. Although treatments to activate T-cell signaling and expansion have been used, activation in general does not alter T-cell subset distribution or preferentially activate antigen-specific T-cells. Importantly, animal models of IMiDs combined with cancer vaccines suggest that these drugs selectively enhance anti-tumor specific T-cell responses. Therefore, we hypothesize that reversal of the T-cell signaling defects and improved T-cell homeostasis with lenalidomide along with a cellular vaccine that is cross-reactive to endogenous tumor antigens should result in an effective therapeutic treatment that will prevent leukemia progression in MDS. To examine the proposed hypothesis, we will perform three specific aims.
In Aim 1, the molecular mechanism of lenalidomide-induced proximal T-cell receptor signaling events will be investigated in vitro. We found that lenalidomide acts as an inhibitor of PP2A phosphatase activity. PP2A is known to bind and possibly repress the YXXM PI3K binding motif in the CD28 receptor intracellular domain that recruits and/or activates proximal signaling intermediates at the level of the T-cell/CD28 pathway. To determine whether inhibition of PP2A repression in the YXXM region is responsible for the co-stimulatory function of lenalidomide, in vitro binding assays, protein tyrosine kinase activation assays, phosphatase function, genetic manipulation of signaling components in primary cells, and overexpression of the CD28 receptor carrying genetic mutations in the YXXM region will be performed.
In Aim 2, studies are designed to identify the mechanisms responsible for changes in T-cell population dynamics in response to leukemia-associated antigens after MDS patients are treated in vivo with lenalidomide therapy. As an ultimate test of our hypothesis, we plan to perform a Phase I dose-escalation trial of the K562 """"""""bystander"""""""" cellular vaccine that is transduced with the genes for GM-CSF and CD40L in combination with the FDA-approved dose of lenalidomide in high-risk MDS patients. The goal of Aim 3 is to determine whether this vaccine/lenalidomide therapy modulates antigen-specific T-cell response against endogenous leukemia-associated antigens present in the bone marrow of MDS patients.
Myelodysplastic syndromes (MDS) are characterized by defective blood formation and high risk for leukemia development and primarily occur in individuals over the age of 65 years old. New strategies of treatment are needed for age-related diseases such as MDS as the US population ages. For tumor vaccine therapies to produce clinical responses in MDS and in cancer patients, appropriate antigen selection, intact antigen presentation, and T-cell function are all critical. We propose a new combination therapy in which a novel cellular vaccine will be combined with a new drug to attack all aspects of this problem. We believe that this new treatment strategy is best tested in the setting of high-risk MDS that generally have poor survival, limited treatment options, and who may have a clinical response to the drug alone. Mechanistic studies will aide our understanding of T-cell immunity and improve our ability to utilize this form of immunotherapy and other forms for the treatment of cancer in general. ? ? ?
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