Engaging and Enhancing Neuroblastoma Immune Targeting

参与和增强神经母细胞瘤免疫靶向

基本信息

批准号：
10401092
负责人：
Kevin A Cassady
金额：
$ 17.32万
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：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10401092
关键词：
Accounting Address Adolescent and Young Adult Adult Antigens Autoantigens Autoimmunity B-Cell Acute Lymphoblastic Leukemia Basic Science Biological Immunotherapy CAR T cell therapy CD19 gene Cancer Center Cancer Model Catalogs Cell Line Cell surface Cessation of life Child Childhood Clinic Clinical Clinical Data Combination immunotherapy Coupled Credentialing Cytolysis DNA Data Development Disease Drops Engineering Environment Flow Cytometry Functional disorder Funding Opportunities Genes Genotype Goals Human Immune Immune Evasion Immune Targeting Immune response Immune system Immunooncology Immunotherapeutic agent Immunotherapy Individual Inter-tumoral heterogeneity Interdisciplinary Study Life MHC Class I Genes MYCN gene Malignant Childhood Neoplasm Malignant Neoplasms Malignant lymphoid neoplasm Manuscripts Mass Spectrum Analysis Mission Modernization Morbidity - disease rate Mus Mutation Neuroblastoma Oncogenes Oncolytic viruses Oncoproteins Outcome Parents Patients Pediatric Hospitals Peptides Phenotype Philadelphia Protein Overexpression Proto-Oncogene Proteins c-myc Public Health Recurrence Refractory Regimen Relapse Research Research Personnel Resistance Resistance development Survival Rate Survivors Sympathetic Nervous System T-Lymphocyte Testing Therapeutic Tissues Toxic effect Translating Translations Treatment Efficacy Tumor Antigens United States National Institutes of Health Up-Regulation Validation Viral Viral Cancer Virotherapy Virus Virus Diseases Work adaptive immune response adaptive immunity anticancer research base cancer cell cancer immunotherapy cancer therapy chimeric antigen receptor T cells clinically relevant cytokine density design experience high risk immunotherapy trials improved in vivo melanoma mortality mouse model multidisciplinary neoplastic cell neuroblastoma cell novel novel therapeutics oncolytic herpes simplex virus overexpression patient derived xenograft model pre-clinical preclinical efficacy recruit success tumor tumor growth 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.

总体总结/摘要儿童癌症研究领域面临着一个重大悖论。几十年前，专注于患有癌症的儿童的先驱研究人员引发了一场革命，导致了以前无法治愈的癌症恶性肿瘤变得可以治愈。相比之下，在过去的二十年里，基础科学不断发展促进对儿科癌症发生的基本了解，但大多数儿科癌症的治愈率恶性肿瘤已经趋于稳定，该领域亲眼目睹了当前的标准疗法通常使幸存者面临治疗引起的危及生命的疾病。令人警醒的是，对于大多数孩子来说复发，很少有新的治疗选择，大多数患者接受相同类型的治疗这首先让他们失望了。博·拜登癌症登月计划带来的融资机会倡议通过成立儿科免疫疗法发现和开发项目来直接解决这一悖论网络（PI-DDN）。 B-ALL 和神经母细胞瘤的免疫疗法现已获得认证，以 CD19 为导向免疫疗法在高度难治性淋巴恶性肿瘤病例中显示出前所未有的活性。这该领域现在已准备好进行集中和持续的多学科努力，以扩大这些早期的成功，并且重新思考我们对儿童癌症的总体治疗方法。在这里，我们提出了儿科免疫肿瘤学儿童最佳免疫治疗策略的发现和发展中心癌症。我们设想该中心为 PI-DDN 提供一个中心枢纽，为多学科研究的共同目标是为儿童创造新的癌症免疫疗法。这中心体现了三个高度集成的多机构项目，由单一的行政和统计核心。这里要测试的首要假设是儿童癌症具有谱系特异性合理有效地靶向肿瘤发生和免疫逃逸机制设计和开发免疫治疗方案。项目 1 将发现谱系特异性细胞表面具有项目定义的用于基于合成免疫治疗的靶向的最佳属性的分子，以及利用它来创建和验证基于高危儿童癌症临床前疗效的新疗法模型。项目 2 将通过开发方法来重点研究免疫疗法耐药性的主要机制规避肿瘤内和肿瘤间异质性以及 T 细胞功能障碍的基本问题内在和外在因素。项目 3 将重点关注儿童和许多成人之间的主要区别恶性肿瘤，其中小儿癌症通常很少引起适应性免疫，并开发治疗方法增强针对儿科癌症特异性抗原靶标的适应性免疫反应。拟议的中心将发现并开发有效的免疫治疗策略，这些策略将立即转化为诊所旨在对儿童癌症结果产生重大直接影响，作为 PI-DDN 的一部分将促进高风险儿科恶性肿瘤的研究进展。