Sunitinib Modulation of Cancer Immunotherapy

舒尼替尼对癌症免疫治疗的调节

• 批准号: 8110572
• 负责人: PETER A COHEN
• 金额: $ 54.87万
• 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/8110572
• 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; Health; 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

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 PUBLIC HEALTH RELEVANCE: This study is an extension of our observation that the anti-angiogenic drug sunitinib (Sutent), which is active in the treatment of kidney cancer, also boosts the immune system by inhibiting cells called myeloid-derived suppressor cells (MDSC). These studies will aim to understand exactly how sunitinib causes improvements in the anti-cancer immune response, how to make sunitinib even more effective against cancers, and how to make sure the immune system is working at its best during sunitinib treatment.

描述（由申请人提供）：受体酪氨酸激酶抑制剂（RTKI）舒尼替尼是转移性mCC（mRCC）的一线治疗药物，但所有患者最终都会对这种抗血管生成药物产生耐药性。与其他RTKI不同，舒尼替尼还可以防止RCC诱导的髓源性抑制细胞（MDSC）的积累，并使1型T细胞功能正常化。我们观察到，无论舒尼替尼治疗期间肿瘤是否消退、稳定或进展，这种显著的免疫调节作用都发生在患者和动物中。尽管如此，在舒尼替尼能够达到其作为免疫调节剂的全部治疗潜力之前，仍然需要解决关键问题，包括肿瘤内MDSC抵抗舒尼替尼的能力，以及舒尼替尼除了MDSC积累之外还抑制树突状细胞（DC）的能力。拟议的研究将采用几种小鼠肿瘤模型以及来自IV期mRCC患者的血液和肿瘤样本，以研究舒尼替尼对小鼠和癌症患者的免疫影响。目的1将描述舒尼替尼阻止肿瘤增强单核细胞-MDSC增殖、嗜中性粒细胞-MDSC分化和嗜中性粒细胞-MDSC存活的机制。目的1还将探索舒尼替尼阻断MDSC发育的这三个步骤是在每个步骤中混杂靶向不同RTK的结果的可能性。目的2将测试肿瘤和骨髓隔室中的MDSC显示出对舒尼替尼的独特抗性的机制，与外周隔室如脾和血液中的MDSC观察到的极端舒尼替尼敏感性形成对比。我们已经初步将这种舒尼替尼耐药性与局部升高的GM-CSF暴露和/或缺氧相关，这导致旁观者MDSC以STAT 3非依赖性方式发展，从而促进舒尼替尼耐药性和局部T细胞功能障碍。目的3将研究舒尼替尼抑制DC和MDSC积累的能力如何影响其在疫苗和过继性T细胞免疫治疗中作为免疫调节剂的用途。我们将开发和测试有效补偿舒尼替尼诱导的宿主DC消耗的免疫治疗策略，并且还旨在克服隔室MDSC对舒尼替尼的耐药性。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道路，优化舒尼替尼在多种肿瘤类型联合免疫治疗中的使用，包括那些可能对舒尼替尼治疗不敏感的血管生成 公共卫生相关性：这项研究是我们观察到的抗血管生成药物舒尼替尼（Sutent）的延伸，舒尼替尼在肾癌治疗中具有活性，也通过抑制称为骨髓源性抑制细胞（MDSC）的细胞来增强免疫系统。这些研究旨在确切了解舒尼替尼如何改善抗癌免疫反应，如何使舒尼替尼对癌症更有效，以及如何确保免疫系统在舒尼替尼治疗期间处于最佳状态。