Local control of anti-tumor/anti-self reactivity in low-affinity ACT

低亲和力 ACT 中抗肿瘤/抗自身反应性的局部控制

基本信息

批准号：
8990833
负责人：
Stephen Philip Schoenberger
金额：
$ 19.25万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-24 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8990833
关键词：
Adoptive Immunotherapy Affinity Animals Antibodies Antigen Targeting Antigens Autoantigens Autoimmune Process Autoimmunity Blood Glucose C57BL/6 Mouse CD8B1 gene CXCL9 gene CXCR3 gene Cancer Patient Cell Count Cell Therapy Cells Chronic Clinical Coupled Cytotoxic T-Lymphocyte-Associated Protein 4 Dendritic Cells Development Distal Effectiveness Employee Strikes Engineering Environment Equilibrium Excision Extramural Activities Goals Health Homing Human Immune Immunity Immunologics Immunotherapy Individual Infiltration Inflammatory Injection of therapeutic agent Interleukin-10 Interleukin-12 Interleukin-2 Interleukin-6 Irradiated tumor Kidney Listeria Malignant Neoplasms Mature B-Lymphocyte Mediating Modeling Modification Monitor Mus Myelogenous National Cancer Institute National Institute of Allergy and Infectious Disease Neoplasm Metastasis Normal Cell Organ Ovarian Carcinoma Pancreas Pathology Patients Peptides Peripheral Primary Neoplasm Proteins Reading Regulatory T-Lymphocyte Research Support Risk Role Signal Transduction Site Specificity Stimulus Suppressor-Effector T-Lymphocytes System T-Cell Receptor T-Lymphocyte TNFRSF5 gene Testing Therapeutic Tissues Toxic effect Transforming Growth Factor beta Translations Tumor Antigens Virus Diseases Work autologous lymphocytes base cancer therapy cancer type cell type chemokine chimeric antigen receptor cytokine immunoregulation in vivo innovation islet macrophage melanocyte mouse model neoplastic cell pre-clinical receptor research study response subcutaneous treatment effect tumor tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): Based significantly on the efforts of both intramural and extramural research supported by the National Cancer Institute (NCI) and the National Institutes of Allergy and Infectious Disease (NIAID), adoptive cellular therapy (ACT) of cancer and chronic viral infections with tumor-infiltrating and receptor-engineered T cells has moved from experimental setting to one of increasing clinical reality. Although transfer of high-affinityT cells holds great promise for a variety of tumor types, their supraphysiologic affinities and antigen sensitivity can cause significant "on-target" immunpathologic damage to self-tissues that share expression of the targeted antigen. A key goal for expanding the efficacy and range of tumors treatable by ACT would be realized by devising ways of controlling the balance between anti-tumor and anti-self-immunity to favor the former. The goal of this exploratory project is to determine whether CD8+ T cells expressing moderate-affinity receptors can be induced to specifically eradicate tumors through immunologic manipulation of their tumor microenvironment without autoimmune damage to healthy self-tissues where such alterations are absent. This work will be carried out in a murine model of ovarian carcinoma (ID8) which features shared expression of a model antigen with both pancreas and kidney in RIP-mOVA mice. ACT will be performed in ID8 tumor-bearing RIP-mOVA mice using moderate affinity OT-3 CD8+ T cells specific for the shared antigen that mirror the post-tolerant repertoire in humans in that they have undergone negative selection and remain ignorant of their cognate peripheral antigen unless they are specifically primed to do so. Aim I will define the therapeutic parameters of tumor control versus on-target autoimmunity by moderate-affinity CD8+ T cells, with the working hypothesis that the threshold for reactivity to both tumor and self is closely coupled. These experiments will examine the role of cell number and priming stimulus in inducing tumor control versus autoimmune destruction of beta islets. Aim II will evaluate whether alterations of tumor microenvironment can allow a number OT-3 cells that is below the threshold for autoimmunity to selectively recognize treated and distal tumors, with the working hypothesis that local immunomodulation can open a window of opportunity for tumor control by moderate affinity T cells. Modifications to be tested in this regard include A) removing inhibitory cell types (regulatory T cells, type 2 macrophages, myeloid-derived suppressor cells) or signals (TGF-β, IL-6, IL-10, PD-1/L1, and CTLA-4), B) enhancing local OT-3 activation with intratumoral immunostimulatory cytokines (IL-2, IL-12) or costimulatory signals (CD27, 4-1BB, CD40), and C) increasing local homing and retention of OT-3 cells by intratumoral injection of CXCR3 chemokines (CXCL9/10). If successful, this project will support a new paradigm that will enable a greatly expanded repertoire of tumor-specific TCRs to be used in ACT, and will greatly decrease the occurrence of on-target toxicities that have limited its application to a broader range of tumor types.

描述（适用提供）：重要的是，国家癌症研究所（NCI）支持的壁内和壁外研究的努力以及国家过敏和传染病（NIAID），癌症和慢性病毒感染的适应性细胞疗法（ACT），肿瘤浸润和受体临床临床临床的癌症和慢性病毒感染已成为现实的实验。尽管高亲和力细胞的转移对各种肿瘤类型具有巨大的希望，但它们的超生理亲和力和抗原敏感性可能会对共享目标抗原表达的自我组织产生重大的“目标”免疫病理损害。通过设计控制反肿瘤和反自身免疫性之间的平衡的方法，可以实现扩大可通过ACT治疗的肿瘤效率和范围的关键目标，以偏爱前者。该探索性项目的目的是确定表达中度亲和力受体的CD8+ T细胞是否可以通过免疫学操纵其肿瘤微环境来特异性放射性肿瘤，而没有自身免疫性损害这种改变的健康自我，而没有自身免疫性损害。这项工作将在卵巢癌模型（ID8）中进行，该模型具有胰腺小鼠中胰腺和肾脏的模型抗原的共同表达。 ACT将使用现代亲和力OT-3 CD8+ T细胞在含ID8肿瘤的RIP-MOVA小鼠中进行，该抗原具有特异性，这些抗原反映了人类的耐耐性后曲目，因为它们已经进行了负面选择，并且除非有特定的剂量。目的我将通过中等亲和力CD8+ T细胞定义肿瘤控制与攻击性自身免疫的治疗参数，并以工作假设是对肿瘤和自我反应性的阈值密切耦合的阈值。这些实验将检查细胞数和启动刺激在诱导的肿瘤控制中与β小岛自身免疫性破坏的作用。 AIM II将评估肿瘤微环境的改变是否可以允许自身免疫性低于阈值的数字OT-3细胞有选择性地识别经过治疗和盘点的肿瘤，并且有效的假设是，局部免疫调节可以通过中等亲和力T细胞为肿瘤控制的机会窗口打开机会窗口。在这方面要测试的修改包括a）a）除去抑制性细胞类型（调节性T细胞，2型巨噬细胞，粒细胞衍生的抑制细胞）或信号（TGF-β，IL-6，IL-6，IL-6，IL-10，PD-1/L1和CTLA-4），b）增强局部OT-3激活的局部OT-3激活cytim-3激活均可用内肿瘤的胞本量均匀脉络化酶促脉络化均经脉络化酶IL-12）或共刺激信号（CD27，4-1BB，CD40）和C）通过肿瘤内注射CXCR3趋化因子（CXCL9/10）来增加局部归巢和保留OT-3细胞。如果成功的话，该项目将支持一种新的范式，该范式将使肿瘤特异性TCR的大幅扩展的曲目用于ACT，并大大降低了靶向毒性的发生，这些靶向毒性限制了其在较广泛的肿瘤类型中的应用。