Sunitinib Modulation of Cancer Immunotherapy

舒尼替尼对癌症免疫治疗的调节

• 批准号: 8449500
• 负责人: PETER A COHEN
• 金额: $ 49.13万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8449500
• 关键词: Address; Adoptive Immunotherapy; Angiogenesis Inhibitors; Animals; BAY 54-9085; Blood; Bone Marrow Neoplasms; Cancer Patient; Cell Differentiation process; Cell Proliferation; Cell Survival; Cell physiology; Cells; Clinical Trials; Commit; Complex; Data; Dendritic Cells; Depressed mood; Development; Dose; Elements; Exposure to; FDA approved; Functional disorder; Future; Generations; Granulocyte-Macrophage Colony-Stimulating Factor; Human; Hypoxia; Imatinib; Immune response; Immune system; Immunologic Adjuvants; Immunomodulators; Immunotherapeutic agent; Immunotherapy; In Vitro; Individual; Location; Malignant Neoplasms; Maximum Tolerated Dose; Mediating; Modeling; Mus; Myelogenous; Patients; Peripheral; Pharmaceutical Preparations; Predisposition; Production; Property; Proto-Oncogene Protein c-kit; Renal Cell Carcinoma; Renal carcinoma; Resistance; Role; STAT3 gene; Sampling; Signal Transduction; Spleen; Staging; Suppressor-Effector T-Lymphocytes; Sutent; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Tyrosine Kinase Inhibitor; Vaccines; Work; cancer immunotherapy; cancer type; experience; healthy volunteer; inhibitor/antagonist; insight; monocyte; next generation; novel therapeutics; peripheral blood; pre-clinical; prevent; receptor; response; tumor; tumor microenvironment

DESCRIPTION (provided by applicant): The receptor tyrosine kinase inhibitor (RTKI) sunitinib is front-line therapy for metastatic mCC (mRCC), yet all patients eventually become resistant to this anti-angiogenic drug. Unlike other RTKIs, sunitinib also prevents RCC-induced accumulation of myeloid derived suppressor cells (MDSC) and normalizes type-1 T cell function. We observed that this remarkable immunomodulatory impact occurs both in patients and animals regardless of whether tumors regress, stabilize or progress during sunitinib therapy. Nevertheless, critical issues remain to be addressed before sunitinib can reach its full therapeutic potential as an immunomodulator, including the capacity of intratumoral MDSC to resist sunitinib, as well as sunitinib's capacity to inhibit dendritic cell (DC) in addition to MDSC accumulation.. The proposed studies will employ several murine tumor models as well as blood and tumor samples from stage IV mRCC patients to investigate sunitinib's immunotherapeutic impacts in both mouse and cancer patients. Aim 1 will delineate the mechanisms by which sunitinib prevents tumor enhancement of monocytic-MDSC proliferation, neutrophilic-MDSC differentiation, and neutrophilic-MDSC survival. Aim 1 will also explore the likelihood that sunitinib's blockade of these three steps of MDSC development is the consequence of promiscuous targeting of different RTKs at each step. Aim 2 will test the mechanism(s) by which MDSC in tumor and bone marrow compartments display distinctive resistance to sunitinib, contrasting to the extreme sunitinib susceptibility observed for MDSC in peripheral compartments such as spleen and blood.. We have tentatively correlated such sunitinib resistance to locally heightened exposure to GM-CSF and/or hypoxia which causes bystander MDSC to develop in a STAT3-independent manner, thus promoting sunitinib resistance and local T cell dysfunction. Aim 3 will investigate how sunitinib's capacity to inhibit DC as well as MDSC accumulation impacts its use as an immunomodulator in the setting of vaccine and adoptive T cell immunotherapy. We will develop and test immunotherapy strategies which effectively compensate for sunitinib-induced host DC depletion, and which also aim to overcome compartmental MDSC resistance to sunitinib. These studies should provide the necessary mechanistic and technical insights to pave a clear path for future clinical trials that optimize sunitinib's use in combination immunotherapy for multliple tumor types, including those which may not be angiogenically susceptible to sunitinib therapy

描述(申请人提供)：受体酪氨酸激酶抑制剂(RTKI)舒尼替尼是治疗转移性MCC(MRCC)的一线药物，但所有患者最终都对这种抗血管生成药物产生抗药性。与其他RTKI不同，舒尼替尼还可以防止肾癌诱导的髓系抑制细胞(MDSC)积聚，并使1型T细胞功能正常化。我们观察到，在舒尼替尼治疗期间，无论肿瘤是消退、稳定还是进展，这种显著的免疫调节影响都会发生在患者和动物身上。然而，在孙尼替尼能够充分发挥其作为免疫调节剂的治疗潜力之前，仍有一些关键问题需要解决，包括肿瘤内MDSC抵抗Sunitinib的能力，以及除了MDSC聚集之外，Sunitinib抑制树突状细胞(DC)的能力。这项拟议的研究将使用几种小鼠肿瘤模型以及来自IV期肾细胞癌患者的血液和肿瘤样本来研究舒尼替尼对小鼠和癌症患者的免疫治疗效果。目的1阐明舒尼替尼抑制肿瘤单核细胞-MDSC增殖、中性粒细胞-MDSC分化和中性粒细胞-MDSC存活的机制。目标1还将探讨Sunitinib对MDSC发展的这三个步骤的封锁是否可能是在每个步骤混杂地针对不同的RTK的结果。目的2将测试肿瘤和骨髓室的骨髓间充质干细胞对舒尼替尼表现出明显耐药的机制(S)，与脾和血液等外周室的骨髓间充质干细胞对舒尼替尼的极端敏感性形成对比。我们初步将这种对局部GM-CSF和/或低氧暴露的耐受性与旁观者MDSC以STAT3非依赖的方式发展相关，从而促进了对苏尼替尼的耐受性和局部T细胞功能障碍。目的3将研究舒尼替尼抑制DC和MDSC聚集的能力如何影响其在疫苗和过继T细胞免疫治疗中作为免疫调节剂的使用。我们将开发和测试免疫治疗策略，有效弥补舒尼替尼诱导的宿主DC耗竭，并旨在克服MDSC对舒尼替尼的隔室耐药。这些研究应该提供必要的机制和技术见解，为未来的临床试验铺平一条明确的道路，以优化舒尼替尼在多种肿瘤类型的联合免疫治疗中的使用，包括那些可能对舒尼替尼治疗不具有血管生成敏感性的肿瘤。