Sunitinib Modulation of Cancer Immunotherapy

舒尼替尼对癌症免疫治疗的调节

• 批准号: 8606436
• 负责人: PETER A COHEN
• 金额: $ 50.16万
• 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 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606436
• 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（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）的一线疗法，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 诱导的骨髓源性抑制细胞 (MDSC) 积累，并使 1 型 T 细胞功能正常化。我们观察到，无论肿瘤在舒尼替尼治疗期间是否消退、稳定或进展，这种显着的免疫调节作用都会发生在患者和动物身上。然而，在舒尼替尼作为免疫调节剂发挥其全部治疗潜力之前，仍需解决一些关键问题，包括肿瘤内 MDSC 抵抗舒尼替尼的能力，以及除了 MDSC 积累之外，舒尼替尼抑制树突状细胞 (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进行研究 舒尼替尼对小鼠和癌症患者的免疫治疗影响。目标 1 将描述舒尼替尼防止肿瘤增强单核细胞 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 还将探讨舒尼替尼对 MDSC 发育这三个步骤的阻断是否是由于每个步骤中不同 RTK 的混杂靶向的结果。目标 2 将测试肿瘤和骨髓区室中的 MDSC 对舒尼替尼表现出独特耐药性的机制，这与在脾脏和血液等外周区室中观察到的 MDSC 的极端舒尼替尼敏感性形成鲜明对比。我们已初步将这种舒尼替尼耐药性与局部增加的 GM-CSF 暴露和/或缺氧相关联，从而导致旁观者 MDSC 在 一种不依赖于 STAT3 的方式，从而促进舒尼替尼耐药和局部 T 细胞功能障碍。目标 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。我们将开发和测试免疫治疗策略，有效补偿舒尼替尼诱导的宿主 DC 耗竭，同时也旨在克服室室 MDSC 对舒尼替尼的耐药性。这些研究应提供必要的机制和技术见解，为未来的临床试验铺平清晰的道路，优化舒尼替尼在多种肿瘤类型联合免疫治疗中的应用，包括那些可能对舒尼替尼治疗血管生成不敏感的肿瘤类型

项目成果

MDSC as a mechanism of tumor escape from sunitinib mediated anti-angiogenic therapy.

• DOI: 10.1016/j.intimp.2011.01.030
• 发表时间: 2011-07
• 期刊: INTERNATIONAL IMMUNOPHARMACOLOGY
• 影响因子: 5.6
• 作者: Finke, James;Ko, Jennifer;Rini, Brian;Rayman, Pat;Ireland, Joanna;Cohen, Peter
• 通讯作者: Cohen, Peter