Discovery and Development of Optimal Immunotherapeutic Strategies for Childhood Cancers

儿童癌症最佳免疫治疗策略的发现和开发

基本信息

批准号：
10578310
负责人：
JOHN M MARIS
金额：
$ 26.4万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-20 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10578310
关键词：
Acute Lymphocytic Leukemia Acute Myelocytic Leukemia Adaptive Immune System Address Adolescent and Young Adult Adult Antigens Basic Science Binding Proteins Brain Neoplasms CD19 gene Cancer Center Cancer Model Cancer Patient Cell surface Chemoresistance Child Childhood Clinic Clinical Clinical Trials Collaborations Credentialing Dependence Development Disease Effector Cell Engineering FDA approved Functional disorder Funding Opportunities Goals Heterogeneity High-Risk Cancer Immune Immune Evasion Immune system Immunooncology Immunosuppression Immunotherapeutic agent Immunotherapy Infiltration Inter-tumoral heterogeneity Interdisciplinary Study Intrinsic factor Leadership Life Lymphocyte MHC Class I Genes Malignant Childhood Neoplasm Malignant Neoplasms Malignant lymphoid neoplasm Mediating Membrane Mission Modernization Molecular Morbidity - disease rate Neuroblastoma Oncogenic Outcome Patients Pediatric Neoplasm Peptides Phase I Clinical Trials Phenotype Physicians Pre-Clinical Model Proteins Public Health Publications Records Refractory Regimen Relapse Research Research Personnel Resistance Resistance development Scientist Signal Transduction Solid Subgroup Survivors T-Lymphocyte Testing Therapeutic Tissues Toxic effect Translating Tumor-infiltrating immune cells United States National Institutes of Health Work adaptive immune response adaptive immunity anti-tumor immune response anticancer research base cancer immunotherapy cancer therapy checkpoint inhibition chemoradiation clinical application design efficacy testing exhaustion experience high risk immune resistance improved innovation mortality multidisciplinary neoplastic cell novel novel therapeutics pediatric immuno-oncology pediatric patients preclinical efficacy prevent rational design sarcoma success tumor tumorigenesis

项目摘要

OVERALL SUMMARY/ABSTRACT There is a major paradox confronting the field of childhood cancer research. Several decades ago, pioneering investigators focused on children with cancer led a revolution resulting in previously incurable malignancies becoming curable. In contrast, over the last two decades, basic science has continued to advance fundamental understanding of the oncogenesis of pediatric cancers, but cure rates for most pediatric malignancies have plateaued, and the field has witnessed first-hand that current standard therapies often saddle survivors with life threatening therapy-induced morbidities. It is sobering that for most children who suffer relapse, few if any novel therapeutic options exist, and most patients receive the same type of therapy that failed them in the first place. The funding opportunity arising out of the Beau Biden Cancer Moonshot initiative directly addresses this paradox by forming a Pediatric Immunotherapy Discovery and Development Network (PI-DDN). Immunotherapy for B-ALL and neuroblastoma is now credentialed, with CD19 directed immunotherapies showing unprecedented activity in highly refractory cases of lymphoid malignancies. The field is now poised for a focused and sustained multi-disciplinary effort to extend these early successes, and rethink our approach to childhood cancer therapy in general. Here, we propose a pediatric immuno-oncology Center entitled Discovery and Development of Optimal Immunotherapeutic Strategies for Childhood Cancers. We envision this Center providing a central hub for the PI-DDN, creating additional opportunities for multi-disciplinary research with the common goal of creating new cancer immunotherapies for children. This Center embodies three highly integrated multi-institutional Projects supported by a single Administrative and Statistical Core. The overarching hypothesis to be tested here is that childhood cancers harbor lineage-specific mechanisms of oncogenesis and immune evasion that can be precisely and effectively targeted by rationally designed and developed immunotherapeutic regimens. Project 1 will discover lineage specific cell surface molecules that have project-defined optimal attributes for synthetic immunotherapeutic based targeting, and use this to create and credential new therapeutics based upon preclinical efficacy in high-risk childhood cancer models. Project 2 will focus on major mechanisms of immunotherapy resistance by developing approaches to circumvent the fundamental issues of intra- and inter-tumoral heterogeneity and T cell dysfunction due to both intrinsic and extrinsic factors. Project 3 will focus on a major difference between pediatric and many adult malignancies, with pediatric cancers typically eliciting little adaptive immunity, and develop approaches to enhance adaptive immune responses against pediatric cancer-specific antigenic targets. The proposed Center will discover and develop effective immunotherapeutic strategies that will be immediately translatable to the clinic, is designed to have a major direct impact on childhood cancer outcomes, and as part of the PI-DDN it will catalyze research advances across the spectrum of high-risk pediatric malignancies.

总体摘要/摘要与儿童癌症研究领域有关的主要悖论。几十年前，专注于癌症儿童的开创性调查人员导致一场革命导致以前无法治愈恶性肿瘤变得可以治愈。相比之下，在过去的二十年中，基础科学继续对小儿癌症的肿瘤发生的基本了解，但是大多数小儿治愈率恶性肿瘤已经平稳，该领域亲眼目睹了当前的标准疗法具有威胁性治疗引起的病态的鞍幸存者。对于大多数孩子来说遭受复发，几乎没有任何新颖的治疗选择，并且大多数患者接受相同类型的治疗首先，这使他们失败了。 Beau Biden Cancer Moonshot产生的资金机会主动性通过形成儿科免疫疗法发现和发展直接解决了这一悖论网络（PI-DDN）。 B-all和神经母细胞瘤的免疫疗法现已证明，CD19定向在高度难治性淋巴恶性肿瘤病例中显示出空前活性的免疫疗法。这现在，Field有望进行集中且持续的多学科努力，以扩大这些早期的成功，并重新考虑我们对儿童癌症治疗的方法。在这里，我们提出了儿科免疫肿瘤学中心名为“发现和开发儿童最佳免疫治疗策略” 癌症。我们设想该中心为PI-DDN提供了一个中心枢纽，为多学科研究的共同目标是为儿童创建新的癌症免疫疗法。这中心体现了三个高度集成的多机构项目，由单个行政和统计核心。这里要检验的总体假设是童年时期的癌症特定于谱系肿瘤发生和免疫逃避的机制，可以由理性地精确有效地针对设计和开发的免疫治疗方案。项目1将发现谱系特定的细胞表面具有基于合成免疫治疗的靶向的项目定义的最佳属性的分子，并且使用此功能根据高风险儿童癌症的临床前疗效创建和证明新的治疗剂型号。项目2将通过开发方法来关注免疫疗法抗性的主要机制避免了肿瘤内和肿瘤间异质性和T细胞功能障碍的基本问题内在和外在因素。项目3将重点关注小儿和许多成年人之间的主要区别恶性肿瘤，儿科癌症通常会引起几乎没有适应性免疫力，并开发出来的方法增强针对小儿癌特异性抗原靶靶标的适应性免疫反应。提议的中心将发现并制定有效的免疫治疗策略，这些策略将立即转换为诊所旨在对儿童癌症的结果产生重大的直接影响，作为Pi-DDN的一部分将催化在高危小儿恶性肿瘤中的研究进展。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

FOXO1 is a master regulator of CAR T memory programming.

FOXO1是CAR T内存编程的主调节器。

DOI：
10.21203/rs.3.rs-2802998/v1
发表时间：
2023
期刊：
Research square
影响因子：
0
作者：
Doan,Alexander;Mueller,KatherineP;Chen,Andy;Rouin,GeoffreyT;Daniel,Bence;Lattin,John;Chen,Yingshi;Mozarsky,Brett;Markovska,Martina;Arias-Umana,Jose;Hapke,Robert;Jung,Inyoung;Xu,Peng;Klysz,Dorota;Bashti,Malek;Quinn,Patrick
通讯作者：
Quinn,Patrick

Human antibodies targeting ENPP1 as candidate therapeutics for cancers.

DOI：
10.3389/fimmu.2023.1070492
发表时间：
2023
期刊：
FRONTIERS IN IMMUNOLOGY
影响因子：
7.3
作者：
Chu, Xiaojie;Baek, Du-San;Li, Wei;Shyp, Taras;Mooney, Brian;Hines, Margaret G.;Morin, Gregg B.;Sorensen, Poul H.;Dimitrov, Dimiter S.
通讯作者：
Dimitrov, Dimiter S.

Proteomic Screens for Suppressors of Anoikis Identify IL1RAP as a Promising Surface Target in Ewing Sarcoma.

DOI：
10.1158/2159-8290.cd-20-1690
发表时间：
2021-11
期刊：
Cancer discovery
影响因子：
28.2
作者：
Zhang HF;Hughes CS;Li W;He JZ;Surdez D;El-Naggar AM;Cheng H;Prudova A;Delaidelli A;Negri GL;Li X;Ørum-Madsen MS;Lizardo MM;Oo HZ;Colborne S;Shyp T;Scopim-Ribeiro R;Hammond CA;Dhez AC;Langman S;Lim JKM;Kung SHY;Li A;Steino A;Daugaard M;Parker SJ;Geltink RIK;Orentas RJ;Xu LY;Morin GB;Delattre O;Dimitrov DS;Sorensen PH
通讯作者：
Sorensen PH

NOT-Gated CD93 CAR T Cells Effectively Target AML with Minimized Endothelial Cross-Reactivity.

DOI：
10.1158/2643-3230.bcd-20-0208
发表时间：
2021-11
期刊：
Blood cancer discovery
影响因子：
11.2
作者：
Richards RM;Zhao F;Freitas KA;Parker KR;Xu P;Fan A;Sotillo E;Daugaard M;Oo HZ;Liu J;Hong WJ;Sorensen PH;Chang HY;Satpathy AT;Majzner RG;Majeti R;Mackall CL
通讯作者：
Mackall CL

Transsulfuration, minor player or crucial for cysteine homeostasis in cancer.