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）Sunitinib是转移性MCC（MRCC）的前线治疗，但所有患者最终都对这种抗血管生成药物具有抵抗力。与其他RTKI不同，Sunitinib还防止了RCC诱导的髓样衍生抑制细胞（MDSC）的积累，并将1型T细胞功能归一化。我们观察到，这种显着的免疫调节作用在患者和动物中都会发生，无论肿瘤在舒尼替尼治疗期间是否会退化，稳定或进展。然而，在夏替尼能够达到其作为免疫调节剂的全部治疗潜力之前，关键问题仍有待解决，包括肿瘤内MDSC抵抗硫替尼的能力，以及Sunitinib抑制树突状细胞（DC）的能力，除了抑制MDSC的累积外，还将调查MRINE TUMOR模型。舒尼替尼在小鼠和癌症患者中的免疫疗法影响。 AIM 1将描述舒尼替尼防止肿瘤增强肿瘤增强，中性粒细胞-MDSC分化和中性粒细胞-MDSC存活的机制。 AIM 1还将探索Sunitinib对MDSC开发的这三个步骤的封锁的可能性是每个步骤滥交靶向不同RTK的结果。 AIM 2将测试肿瘤和骨髓室中MDSC对舒尼替尼表现出独特的抵抗力的机制，与在脾周围室中MDSC（如脾和血液）中观察到的极端舒尼替尼的敏感性（如脾和血液）相比。与STAT3无关的方式，从而促进了舒尼替尼的抗性和局部T细胞功能障碍。 AIM 3将调查舒尼替尼在疫苗和收养T细胞免疫疗法的情况下抑制直流和MDSC积累的能力以及MDSC积累的影响。我们将制定和测试免疫疗法策略，以有效地弥补舒尼替尼引起的宿主DC耗竭，并旨在克服隔室MDSC对Sunitinib的耐药性。这些研究应提供必要的机械和技术见解，为将来的临床试验铺平一条清晰的途径，以优化Sunitinib在组合免疫疗法中用于多肿瘤类型的使用，包括那些可能对Sunitinib疗法敏感的那些肿瘤类型。

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