Thursday, April 25, 2024
4/25/2024
PROJECT SUMMARY Although chemotherapy can induce remission in patients with acute leukemia, it is often met with high probability of relapse. There is currently an unmet need for alternative therapeutic approaches that effectively prevent relapse or that can be used to treat relapsed or refractory disease. Overwhelming evidence suggests that the success of allogeneic hematopoietic stem cell transplantation to sustain complete remission in leukemia patients relies on the presence of tumor-specific T cell immunity (graft-versus-leukemia effect). Wilms tumor 1 (WT1) is overexpressed in nearly all pediatric and adult acute leukemias with evidence of WT1-specific CD8+ T cells spontaneously arising in patients, highlighting its potential as a universal leukemia- specific antigen. Our long-term goal is to develop an immunotherapeutic strategy incorporating full-length WT1 antigen to induce robust, anti-leukemic immunity in patients. The overall objective of this application is to determine the utility of our Salmonella-based therapeutic, shIDO-ST, in eliciting WT1-specific immunity through a unique population of antigen-presenting, polymorphonuclear neutrophils (APC-PMN). APC-PMN can be generated in vitro by culturing of PMN with granulocyte macrophage-colony stimulating factor (GM-CSF) and have been shown to prime T cell responses to foreign and cancer-associated antigens. Our central hypothesis is that incorporating the WT1 transgene into shIDO-ST (WT1-shIDO-ST) will facilitate the coordinate generation of hybrid APC-PMN presenting WT1 epitopes to induce effective anti-leukemic immunity. Our hypothesis has been formulated on the basis of our own preliminary data confirming the ability of shIDO-ST treatment to generate APC-PMNs in vivo that are capable of priming antigen-specific T cell responses. The rationale for the proposed research is that a greater breadth of WT1-specific responses elicited by WT1-shIDO-ST therapy represents a universal approach for treating leukemia patients. The central hypothesis and overall objective will be tested by pursuing two specific aims: 1) Identify key features of WT1-specific immunity induced by WT1- shIDO-ST therapy and 2) Determine the therapeutic efficacy of WT1-shIDO-ST treatment in leukemia models. Targeting the most abundant leukocyte in the body to generate APC-PMN while also harnessing their antigen- presenting functions are innovative aspects of our study. The proposed research is significant because it offers a novel approach to elicit WT1-specific immunity and can be extended to incorporate antigens specific to other malignancies or infectious diseases. Thus, this work will develop foundational resources that can be used by researchers seeking to elicit antigen-specific responses in the prophylactic or therapeutic setting. The proximate expected outcome of this work will be a greater understanding of the immune subsets contributing to WT1- specific immunity, following WT1-shIDO-ST treatment, and their potential to eliminate leukemic cells. The results of this study will have an important positive impact because they will establish a novel approach to elicit antigen- specific responses, which in the long-term offers an alternative immunotherapeutic strategy for many diseases.
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