Utilizing Hybrid Antigen-Presenting Neutrophils to Prime WT1-Specific Immune Responses as Therapy for Acute Leukemia

利用混合抗原呈递中性粒细胞引发 WT1 特异性免疫反应作为急性白血病的治疗

• 批准号: 10373124
• 负责人: EDWIN MANUEL
• 金额: $ 24.68万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373124
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Adult; Allogenic; Antigen Presentation; Antigens; CD8-Positive T-Lymphocytes; Cell Line; Childhood; Communicable Diseases; Culture Media; Data; Developing Countries; Disease; Disease remission; Disease-Free Survival; Epitopes; Foundations; Generations; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; HLA-A2 Antigen; Hematopoietic Stem Cell Transplantation; Heterogeneity; Hybrids; Ideal 1; Immune; Immune response; Immunity; Immunotherapeutic agent; In Vitro; In complete remission; Intravenous; Length; Leukemia in Remission; Leukemic Cell; Leukocytes; Malignant Neoplasms; Methods; Modeling; Monitor; Mus; National Cancer Institute; Natural regeneration; Outcome; Patients; Peptide Vaccines; Phase II Clinical Trials; Population; Probability; Production; Public Health; Recurrent disease; Refractory; Refractory Disease; Relapse; Research; Research Personnel; Resources; Role; Salmonella; Survival Rate; T cell response; T-Lymphocyte; Testing; Therapeutic; Transgenes; Treatment Efficacy; Tryptophan 2,3 Dioxygenase; WT1 gene; Work; antigen-specific T cells; base; cancer therapy; chemotherapy; chronic leukemia; cost; graft vs leukemia effect; high risk; in vivo; innovation; insight; leukemia; leukemic stem cell; microbial; neoantigens; neutrophil; novel; novel strategies; novel therapeutic intervention; overexpression; patient prognosis; peptide vaccination; prevent; prophylactic; relapse patients; relapse risk; response; risk minimization; success; therapeutic target; transcription factor; tumor

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.

项目摘要 虽然化疗可以使急性白血病患者得到缓解，但通常 复发的可能性很高。目前对替代治疗方法的需求尚未得到满足 有效预防复发或可用于治疗复发或难治性疾病。压倒 有证据表明，同种异体造血干细胞移植的成功可以维持完整的 白血病患者的缓解依赖于肿瘤特异性 T 细胞免疫（移植物抗白血病 影响）。肾母细胞瘤 1 (WT1) 在几乎所有儿童和成人急性白血病中过度表达，有证据表明 WT1 特异性 CD8+ T 细胞在患者体内自发产生，凸显了其作为通用白血病的潜力 特异性抗原。我们的长期目标是开发一种结合全长 WT1 的免疫治疗策略 抗原诱导患者产生强大的抗白血病免疫力。该应用程序的总体目标是 确定我们基于沙门氏菌的治疗剂 shIDO-ST 在通过以下方式引发 WT1 特异性免疫方面的效用 一个独特的抗原呈递群体，多形核中性粒细胞（APC-PMN）。 APC-PMN 可以是 通过用粒细胞巨噬细胞集落刺激因子 (GM-CSF) 培养中性粒细胞 (PMN) 在体外产生 已被证明可以引发 T 细胞对外来抗原和癌症相关抗原的反应。我们的中心假设 将 WT1 转基因纳入 shIDO-ST (WT1-shIDO-ST) 将促进坐标生成 混合 APC-PMN 呈递 WT1 表位以诱导有效的抗白血病免疫。我们的假设有 是根据我们自己的初步数据制定的，证实了 shIDO-ST 治疗的能力 在体内产生能够引发抗原特异性 T 细胞反应的 APC-PMN。理由如下： 拟议的研究表明，WT1-shIDO-ST 疗法可引发更广泛的 WT1 特异性反应 代表了治疗白血病患者的通用方法。中心假设和总体目标将 通过追求两个具体目标进行测试：1) 确定 WT1- 诱导的 WT1 特异性免疫的关键特征 shIDO-ST 治疗和 2) 确定 WT1-shIDO-ST 治疗在白血病模型中的治疗效果。 针对体内最丰富的白细胞生成 APC-PMN，同时利用其抗原- 呈现功能是我们研究的创新方面。拟议的研究意义重大，因为它提供了 一种引发 WT1 特异性免疫的新方法，并且可以扩展到合并其他特异性抗原 恶性肿瘤或传染病。因此，这项工作将开发可供以下人员使用的基础资源： 研究人员寻求在预防或治疗环​​境中引发抗原特异性反应。近处的 这项工作的预期成果将是更好地了解有助于 WT1-的免疫子集 WT1-shIDO-ST 治疗后的特异性免疫及其消除白血病细胞的潜力。结果 这项研究将产生重要的积极影响，因为他们将建立一种新的方法来引发抗原- 特异性反应，从长远来看，这为许多疾病提供了替代的免疫治疗策略。