Optimizing Induction Conditions for Immunotherapeutic CTL

优化免疫治疗 CTL 的诱导条件

基本信息

批准号：
8704325
负责人：
Robert M Prins
金额：
$ 38.26万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-13 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8704325
关键词：
Adoptive Transfer Affect Agonist Antigen-Presenting Cells Antigens Apoptosis Autoantigens Autologous Biocompatible Biological Assay Bone Marrow Brain Neoplasms C Type Lectin Receptors C57BL/6 Mouse Cancer Vaccines Cell Culture Techniques Cells Characteristics Clinical Clinical Research Complex Culture Media Cytolysis Cytotoxic T-Lymphocytes DNA Dendritic Cell Vaccine Dendritic Cells Dendritic cell activation Effector Cell Elements Generations Glioma Goals Imiquimod Immature Bone Immunologist Immunotherapeutic agent Immunotherapy In Vitro Individual Letters Ligands Light Lymphocyte MHC Class I Genes Measures Mixed Neoplasm Modeling Morphology Mus Nature Particle Size Pattern recognition receptor Peptides Preparation Production Radio Reaction Research Research Design Research Personnel Serum Signaling Molecule Splenocyte Staining method Stains Stimulus Surface T-Lymphocyte Techniques Testing Therapeutic Uses Toll-like receptors Tumor Antigens Tumor Stem Cells Vaccines Work cancer immunotherapy cancer therapy carcinogenesis cell injury clinical application computerized cytokine cytotoxic cytotoxicity experience in vivo interest mouse model nanomedicine nanoparticle neoplastic cell pathogen precursor cell public health relevance research study response screening stem cell therapy success therapy resistant translational medicine tumor

项目摘要

DESCRIPTION (provided by applicant): The project goals are 1) to develop biocompatible nanoparticles (NP) bearing Pattern Recognition Receptor (PRR) molecules, i.e., agonists for Toll Like Receptors or C-type Lectin Receptors, 2) to determine if these NP- PRR differently affect activation of dendritic cells (DC), 3) to determine if the differently activated DC then influence the generation and functionality of T effector cells, and 4) to evaluate the alloreactive CTL and the autologous tumor associated antigen (TAA)-directed CTL in the GL261 mouse glioma model, where the tumor cell inoculum either is or is not enriched for brain tumor stem cells (BTSC). The latter goal will allow for a determination of BTSC immunosensitivity/immunoresistance. The cancer immunotherapy approach will: "Use various NP-PRR (CpG DNA, imiquimod, LPS and mannosylated BSA) that will be components of a biocompatible PLGA carrier matrix already approved for clinical use to stimulate DC to variable activation states. In some experiments complex NP-PRR will also contain tumor associated antigens (mEphA2, hgp100, mTRP-2 and GARC-1) " Use conventional and Flt3 ligand DC derived from immature bone marrow (BM) as precursor cells " NP-PRR activated DC will then be used to stimulate alloreactive or autologous naive T cells to effector cytotoxic T lymphocytes (CTL) "NP-PRR stimulated DC and subsequently stimulated CTL will be functionally and phenotypically characterized in vitro."Stimulated alloreactive CTL or TAA-directed CTL will be functionally and phenotypically characterized for their antitumor effects after their adoptive transfer into mice bearing serum-cultured GL261 or the neurosphere-cultured counterpart.

描述（由申请人提供）：项目目标是1）开发生物相容性的纳米颗粒（NP）轴承模式识别受体（PRR）分子，即，像受体或C型凝集素受体的激动剂，2）是否确定这些NP是否是这些NP - PRR对树突状细胞（DC）的激活有所不同，为确定不同激活的DC是否会影响T效应细胞的产生和功能，以及4）评估同种反应性CTL和自体肿瘤相关抗原（TAA） - 在GL261小鼠胶质瘤模型中定向CTL，其中肿瘤细胞接种物是或不富含脑肿瘤干细胞（BTSC）的肿瘤细胞。后一个目标将允许确定BTSC免疫敏感/免疫阻力。癌症免疫疗法方法将：“使用各种NP-PRR（CPG DNA，咪喹莫德，LPS和甘露糖基化的BSA），它们将是生物相容性的PLGA载体基质的组成部分，这些载体矩阵已批准已批准用于临床用途，以刺激DC到可变激活状态。 NP-PRR还将包含肿瘤相关的抗原（MEPHA2，HGP100，MTRP-2和GARC-1）“使用源自未成熟骨髓（BM）的常规和FLT3配体DC作为前体细胞” NP-PRR激活的DC将被使用为了刺激同种反应性或自体天真T细胞，可效应细胞毒性T淋巴细胞（CTL）“ NP-PRR刺激的DC并随后刺激的CTL在功能和表型上在体外表征。对于它们的抗肿瘤作用，它们的收养转移到带有血清培养的GL261或神经圈培养的小鼠的小鼠中。