Novel Strategies for Cancer Immunotherapy in Stem Cell Transplant

干细胞移植中癌症免疫治疗的新策略

• 批准号: 9056978
• 负责人: Yiping Yang
• 金额: $ 35.78万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9056978
• 关键词: Adoptive Transfer; Agonist; Alloantigen; Allogenic; Antigen-Presenting Cells; Cells; Clonal Expansion; Contact hypersensitivity; Development; Disease; Elements; Engraftment; Generations; Half-Life; Haptens; Health; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Histocompatibility Antigens Class I; Homologous Transplantation; Immune system; Immunologic Memory; Infection; Knowledge; Learning; Life; Liver; Lymphoid; Malignant Neoplasms; Mediating; Memory; Modeling; Molecular; Morbidity - disease rate; Mus; Natural Killer Cells; Neoplasm Metastasis; Organ; Outcome; Outcome Study; Patients; Phase; Population; Property; Receptor Signaling; Recurrence; Risk; Role; Secondary to; Signal Transduction; Stem cell transplant; T-Cell Depletion; T-Lymphocyte; Testing; Time; Toll-like receptors; Tumor Immunity; Vaccinia virus; Vesicular stomatitis Indiana virus; Virus Diseases; adaptive immunity; antitumor effect; base; cancer immunotherapy; cancer prevention; cancer therapy; cancer type; curative treatments; cytokine; design; graft vs host disease; influenzavirus; killings; mortality; mouse model; neoplastic cell; novel strategies; novel therapeutic intervention; prevent; receptor; response; tumor

DESCRIPTION (provided by applicant): Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for many types of hematologic malignancies. However, graft-versus-host disease (GVHD) mediated by alloreactive T cells remains the most common cause of nonrelapse-related morbidity and mortality after allo-HSCT. Although T cell depletion and other strategies of reducing T cell alloreactivity are effective in the control of GVHD, they are often associated with increased risks of tumor recurrence. Thus, it is compelling to develop strategies for enhancing anti-tumor effect without GVHD. Studies have shown that donor natural killer (NK) cell alloreactivity can exert anti-tumor effect while protecting patients against GVHD. However, it is not clear whether these donor-derived alloreactive NK cells can persist to become long-lived memory cells and protect hosts from tumor recurrence. Although immunological memory has been thought to be a hallmark of adaptive immunity, recent advance has suggested that specific subsets of NK cells can develop into long-lived and specific memory cells in models of hapten-induced contact hypersensitivity and viral infections. In a murine model of allogeneic transplantation, we showed in the preliminary studies that alloreactive NK cells can persist for a long time, possess the properties of memory cells and protect against a secondary tumor challenge. The objective of this application is to understand the mechanisms underlying the formation of alloreactive memory NK cells. We hypothesize that multiple signals are required for the formation of alloreactive NK cell memory. We will test this hypothesis with four specific aims and pursue critical elements required for the formation of alloreactive memory NK cells. By providing molecular and cellular basis for the formation of alloreactive NK cell memory, these studies will have profound implications in the development of new therapeutic strategies for cancer prevention and therapy in the setting of allogeneic stem cell transplantation. Furthermore, the principles learned here can be applied to the NK cell memory field in general for the treatment of other diseases such as pathogenic infections.

描述（由申请人提供）：同种异体造血干细胞移植（Allo-HSCT）是许多类型的血液系统恶性肿瘤的潜在治疗疗法。然而，同种反应性T细胞介导的移植物抗宿主病（GVHD）仍然是异抗HSCT之后与非蠕动相关的发病率和死亡率的最常见原因。尽管T细胞的耗竭和其他降低T细胞同质反应性的策略可有效控制GVHD，但它们通常与肿瘤复发风险增加有关。因此，令人信服的是制定没有GVHD的抗肿瘤效应的策略。研究表明，供体天然杀手（NK）细胞同质性可以发挥抗肿瘤作用，同时保护患者 反对GVHD。但是，尚不清楚这些供体衍生的同种异体NK细胞是否可以持续成为长寿命的记忆细胞并保护宿主免受肿瘤复发。尽管已经认为免疫记忆是适应性免疫的标志，但最近的进步表明，在触觉诱导的接触超敏反应和病毒感染模型中，NK细胞的特定子集可以发展为长寿和特定的记忆细胞。在同种异体移植的鼠模型中，我们在初步研究中表明，同种异体NK细胞可以持续很长时间，具有记忆细胞的特性并预防二次肿瘤挑战。该应用的目的是了解同种反应性记忆NK细胞形成的基础机制。我们假设形成同种异体NK细胞存储器需要多个信号。我们将以四个特定的目标检验这一假设，并追求形成同种异体记忆NK细胞所需的关键要素。通过为形成同种异体NK细胞记忆的形成分子和细胞基础，这些研究将对在同种异体干细胞移植的情况下对新的预防癌症预防和治疗的新治疗策略产生深远的影响。此外，这里学到的原则通常可以应用于NK细胞记忆场，以治疗其他疾病，例如致病感染。