Slow cycling cell RNA based T cell therapy to prevent recurrence in GBM

基于慢循环细胞 RNA 的 T 细胞疗法可预防 GBM 复发

基本信息

批准号：
10331046
负责人：
Loic Pierre Deleyrolle
金额：
$ 22.88万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10331046
关键词：
Adjuvant Therapy Adoptive Cell Transfers Animals Antigens Autologous Automobile Driving Biology Brain Neoplasms Cell Cycle Cells Chemoresistance Clinical Clinical Treatment Clinical Trials Collecting Cell Dendritic Cells Development Disease Disease model Environment Evolution Excision Glioblastoma Glioma Goals Human Immune Immune Targeting Immune response Immune system Immunologics Immunology Immunotherapy In Vitro Interferons Intravenous Investigation Investigational Therapies Laboratories Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Modality Modeling Mononuclear Mus Mutate Nature Neuraxis Operative Surgical Procedures Pathogenicity Patients Peptides Peripheral Peripheral Blood Mononuclear Cell Phenotype Physiologic pulse Play Population Pre-Clinical Model Prognosis Protocols documentation RNA Radiation Radiation therapy Radio Recurrence Recurrent disease Recurrent tumor Refractory Regimen Relapse Reporting Research Residual state Resistance Role Running Severities Source Specificity Surveys System T cell therapy T-Cell Activation T-Lymphocyte Testing Therapeutic Treatment Efficacy Tumorigenicity Vaccines anticancer treatment antigen-specific T cells base cancer therapy clinically relevant conventional therapy cytotoxic design efficacy testing experimental study glioma cell line immunogenic immunogenicity improved in vivo innovation mouse model neoantigens neoplastic cell novel novel strategies prevent recruit refractory cancer self-renewal slow potential temozolomide therapy resistant tumor tumor progression

项目摘要

PROJECT SUMMARY AND ABSTRACT Conventional cancer treatments target fast-cycling cells, however slowly dividing populations tend to be spared recapitulating the tumor via their self-renewing abilities. We reported the existence of slow-cycling cells (SCCs) that are extremely resistant to therapies and play a critical role in recurrence of glioblastoma (GBM). Clinical strategies able to target this specific phenotype hold great promises for improving prognosis. Importantly, these pathogenic drivers demonstrated expression of predicted immunogenic antigens providing therapeutic opportunities that we propose to exploit in the context of immunotherapy. We have established a new platform for adoptive cellular therapy (ACT) employing the use of total tumor RNA-pulsed dendritic cells (DCs) to expand tumor reactive T lymphocytes. We are currently testing in multiple clinical trials this treatment modality in patients with brain tumors (ACTION-IND#17298, REMATCH-IND#14058, BRAVO-IND#17298). The goal of this project is to leverage the power of this therapeutic platform to achieve robust targeting of treatment-resistant clones using a novel model of recurrent GBM. We hypothesize that the cytotoxic activity of tumor-specific T cells can be directed toward clones promoting recurrence by SCC RNA-pulsed dendritic cells, thus impeding disease relapse. To test our hypothesis, the specific aims of this proposal are to: Aim 1. Determine the immunogenicity and efficacy of slow-cycling cell RNA-based T cell treatment in a preclinical model of recurrent GBM Aim 2. Evaluate the slow-cycling cell RNA-based T cell platform in a human autologous setting. Successfully completed, this proposal has a strong likelihood to impact favorably on treatment options for patients with malignant gliomas.

项目概要和摘要传统的癌症治疗针对的是快速循环的细胞，但缓慢分裂的细胞群往往可以幸免通过它们的自我更新能力来重现肿瘤。我们报告了慢循环细胞（SCC）的存在它们对治疗具有极强的抵抗力，并且在胶质母细胞瘤（GBM）的复发中发挥着关键作用。临床能够针对这种特定表型的策略有望改善预后。重要的是，这些致病驱动因素证明了预测的免疫原性抗原的表达，从而提供了我们建议在免疫疗法的背景下利用的治疗机会。我们已经建立了一个使用总肿瘤 RNA 脉冲树突状细胞进行过继细胞治疗 (ACT) 的新平台 (DC) 扩增肿瘤反应性 T 淋巴细胞。我们目前正在多项临床试验中测试这种治疗方法脑肿瘤患者的治疗方式（ACTION-IND#17298、REMATCH-IND#14058、BRAVO-IND#17298）。该项目的目标是利用该治疗平台的力量来实现强有力的靶向使用一种新的复发性 GBM 模型来克隆治疗耐药性。我们假设细胞毒活性肿瘤特异性 T 细胞可以被 SCC RNA 脉冲的树突状细胞引导至促进复发的克隆，从而阻止疾病复发。为了检验我们的假设，该提案的具体目标是：目标 1. 在临床前确定基于慢循环细胞 RNA 的 T 细胞治疗的免疫原性和功效复发性GBM模型目标 2. 在人类自体环境中评估基于 RNA 的慢循环细胞 T 细胞平台。如果成功完成，该提案很可能会对以下患者的治疗选择产生有利影响：恶性胶质瘤患者。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Comment on Mahajan, S.; Schmidt, M.H.H. Distinct Lineage of Slow-Cycling Cells Amidst the Prevailing Heterogeneity in Glioblastoma. Cancers 2023, 15, 3843.

DOI：
10.3390/cancers16020277
发表时间：
2024-01-09
期刊：
CANCERS
影响因子：
5.2
作者：
Yang, Changlin;Mitchell, Duane A.;Deleyrolle, Loic P.
通讯作者：
Deleyrolle, Loic P.

KR158 spheres harboring slow-cycling cells recapitulate GBM features in an immunocompetent system.

含有慢循环细胞的 KR158 球体再现了免疫活性系统中的 GBM 特征。

DOI：
10.1101/2024.01.26.577279
发表时间：
2024
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Chakraborty,Avirup;Yang,Changlin;Kresak,JesseL;Silver,Aryeh;Feier,Diana;Tian,Guimei;Andrews,Michael;Sobanjo,OlusegunO;Hodge,EthanD;Engelbart,MiaK;Huang,Jianping;Harrison,JeffreyK;Sarkisian,MatthewR;Mitchell,DuaneA;Deleyr
通讯作者：
Deleyr

Heterogeneity of glioblastoma stem cells in the context of the immune microenvironment and geospatial organization.

DOI：
10.3389/fonc.2022.1022716
发表时间：
2022
期刊：
FRONTIERS IN ONCOLOGY
影响因子：
4.7
作者：
Silver, Aryeh;Feier, Diana;Ghosh, Tanya;Rahman, Maryam;Huang, Jianping;Sarkisian, Matthew R.;Deleyrolle, Loic P.
通讯作者：
Deleyrolle, Loic P.