Targeting SOCS1 and RASA2 to Engineer More Potent Adoptive T Cell Therapies for Cancer Treatment.

以 SOCS1 和 RASA2 为靶点，设计更有效的过继 T 细胞疗法来治疗癌症。

基本信息

批准号：
10216208
负责人：
JULIA Catherine CARNEVALE
金额：
$ 26.33万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10216208
关键词：
Adoptive Cell Transfers Affect Antigens Antitumor Response Area Attenuated Award Basic Science Biological CAR T cell therapy CD19 gene CRISPR screen CTAG1 gene Cancer Center Cancer Patient Candidate Disease Gene Cell physiology Cells Cellular biology Characteristics Chemicals Clinic Clinical Clinical Trials Combined Modality Therapy Complement Educational workshop Electroporation Engineering Evaluation Foundations Funding Gene Combinations Gene Targeting Genes Genetic Transcription Genome Genome engineering Goals Human Immune Immune system Immunocompetent Immunodeficient Mouse Immunomodulators Immunotherapy Implant In Vitro Infection Knock-out Laboratories Libraries MAP Kinase Gene Malignant Neoplasms Melanoma Cell Membrane Proteins Mentors Mentorship Methods Mitogen-Activated Protein Kinases Modeling Molecular Mus Oncology Pathway interactions Patients Performance Phenotype Pre-Clinical Model Property Publishing Research Research Personnel SILV gene Signal Transduction Solid Neoplasm Spleen Structure System T cell response T cell therapy T-Cell Activation T-Cell Proliferation T-Lymphocyte Technology Testing Therapeutic Training Translational Research Tumor Immunity cancer cell cancer immunotherapy cancer therapy career cell behavior cell killing cellular transduction effective therapy engineered T cells experience gene discovery genome wide screen genome-wide hands on research immune checkpoint improved in vivo in vivo Model inhibitor/antagonist interest lead candidate mouse model neoplastic cell next generation next generation sequencing novel pre-clinical preclinical evaluation programs research clinical testing response screening single-cell RNA sequencing skills synergism tool tumor

项目摘要

The goal of this K08 application is to provide Dr. Julia Carnevale, MD, with the skills she will need to become an independently-funded laboratory investigator studying novel ways to engineer T cells with more potent anti-tumor activity. There is intense clinical interest in improving adoptive T cell therapies to treat and cure more cancers. However, until recently there has been no way to efficiently and comprehensively evaluate the genome to find the critical gene networks that can be leveraged to program favorable human T cell behaviors. Dr. Carnevale recently developed a novel screening technology, sgRNA lentiviral infection with CAS9 electroporation (SLICE), that enables genome-wide CRISPR screening in primary human T cells to search for genes that regulate key therapeutic functions. Dr. Carnevale used SLICE to perform a genome-wide screen in T cells which identified a host of regulators of proliferation, many of which also enhanced T cell activation and in vitro cancer cell killing. She now proposes targeting top-raking genes from this screen, SOCS1 and RASA2 (negative regulators of JAK/STAT and MAP kinase signaling, respectively), to improve the efficacy of adoptive T cell therapies. She hypothesizes that disruption of SOCS1 or RASA2 will enhance the anti-tumor properties of human T cells, that these genes can be targeted to improve adoptive T cell therapies, and that SLICE pooled screening can be performed in vivo to identify modifier gene targets that synergize with SOCS1 and RASA2 loss to improve tumor control. The specific aims of the proposed research are: 1) to test how SOCS1 and RASA2 influence T-cell responses to repeated stimulation and explore the molecular pathways that govern these responses, 2) to determine the effects of SOCS1 or RASA2 inactivation on antitumor activities of T cells in vivo, and 3) to identify gene targets that synergize with SOCS1 or RASA2 loss in vivo. Dr. Carnevale's training and research plans includes a combination of structured coursework and workshops, one-on-one tutorials, and hands-on research experience that will all take place at UCSF, a world-renowned academic center of excellence in basic and translational research. Dr. Carnevale's training plan will complement her existing expertise to build a strong foundation in the following areas: 1) fundamental T cell biology including the study of regulatory circuitry, function, and tumor immunity, 2) preclinical modeling of adoptive T cell therapies, and 3) next-generation sequencing methods and analysis including single-cell RNA sequencing. This project will be conducted under the mentorship of her primary mentor, Dr. Alan Ashworth, President of the UCSF Cancer Center and world expert in therapeutic discovery and translational research, and her co-mentor, Dr. Alex Marson, leading expert in genome engineering in immune cells. She will also receive extensive input from her distinguished advisory panel with complementary expertise to guide her research and career trajectory. At the completion of this award, Dr. Carnevale will have the relevant didactic and research experience to become a leader in discovering and developing next-generation adoptive T cell therapies for cancer patients.

该K08申请的目的是向医学博士朱莉娅·卡内维尔博士提供她将要有的技能需要成为一名独立资助的实验室研究者，研究新颖的方法来设计具有更有效抗肿瘤活性的细胞。在改善方面有强烈的临床兴趣收养T细胞疗法以治疗和治愈更多的癌症。但是，直到最近还没有有效，全面评估基因组以找到关键基因网络的方法可以利用以编程有利的人类T细胞行为。卡内维尔博士最近开发了新型筛查技术，SGRNA慢病毒感染，带有Cas9电穿孔（切片），在原代人T细胞中启用全基因组CRISPR筛选，以搜索调节钥匙的基因治疗功能。 Carnevale博士使用切片在T细胞中进行全基因组筛查确定了许多增殖的调节剂，其中许多也增强了T细胞的激活和体外癌细胞杀死。她现在建议从这个屏幕上瞄准顶级基因，SOCS1 和RASA2（分别为JAK/STAT的负调节剂和MAP激酶信号传导），以改善收养T细胞疗法的功效。她假设SOCS1或RASA2的破坏将增强人类T细胞的抗肿瘤特性，可以将这些基因靶向改善收养T细胞疗法，并且可以在体内进行切片汇总筛选以识别改性基因靶向与SOCS1和RASA2损失协同作用以改善肿瘤控制的目标。这拟议研究的具体目的是：1）测试SOCS1和RASA2如何影响T细胞对重复刺激的反应并探索控制这些刺激的分子途径响应，2）确定SOCS1或RASA2失活对抗肿瘤活动的影响 T细胞在体内和3）确定与体内SOCS1或RASA2损失协同的基因靶标。卡尼维尔博士的培训和研究计划包括结构化课程和讲习班，一对一的教程和动手研究经验都将在 UCSF，一个世界知名的基础和转化研究卓越学术中心。卡内维尔博士的培训计划将补充她现有的专业知识，以建立强大的基础在以下领域：1）基本的T细胞生物学，包括调节回路的研究，功能和肿瘤免疫，2）养子T细胞疗法的临床前建模，3）下一代测序方法和分析，包括单细胞RNA测序。这个项目将在其主要导师的指导下进行，主席Alan Ashworth博士 UCSF癌症中心以及治疗发现和翻译研究的世界专家，她联合学者Alex Marson博士，免疫细胞基因组工程领域的主要专家。她也会从她杰出的咨询小组中获得丰富的意见，并具有互补的专业知识来指导她的研究和职业轨迹。该奖项完成后，卡内维尔博士将拥有相关的教学经验和研究经验，成为发现和发展的领导者癌症患者的下一代产物T细胞疗法。