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

• 批准号: 10217467
• 负责人: JOHN M MARIS
• 金额: $ 18.4万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 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/10217467
• 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; 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 patients; preclinical efficacy; prevent; sarcoma; success; tumor; tumorigenesis

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的矛盾。几十年前， 专注于儿童癌症的先驱研究人员领导了一场革命， 恶性肿瘤可以治愈相比之下，在过去的二十年里，基础科学继续 促进对儿童癌症发生的基本理解，但大多数儿童癌症的治愈率 恶性肿瘤已经趋于稳定，并且该领域已经亲眼目睹了当前的标准疗法通常 使幸存者面临威胁生命的治疗诱发的疾病。令人清醒的是，对于大多数 复发，很少有新的治疗选择存在，大多数患者接受相同类型的治疗 一开始就让他们失望了Beau Biden Cancer Moonshot项目带来的融资机会 该倡议通过成立儿科免疫疗法发现和开发项目， 网络（PI-DDN）。B-ALL和神经母细胞瘤的免疫疗法现在获得认证，CD 19指导 免疫疗法在淋巴恶性肿瘤的高度难治性病例中显示出前所未有的活性。的 该领域现在正准备集中和持续的多学科努力，以扩大这些早期的成功， 重新思考我们对儿童癌症的治疗方法。在这里，我们提出了一个儿科免疫肿瘤学 儿童最佳免疫策略的发现和发展中心 癌的我们设想该中心为PI-DDN提供一个中心枢纽，为以下方面创造更多机会： 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一体化的多机构项目，由一个单一的行政和 统计核心。这里要检验的首要假设是，儿童癌症具有谱系特异性， 肿瘤发生和免疫逃避的机制，可以通过合理的方法精确有效地靶向 设计并开发了免疫疗法。项目1将发现谱系特异性细胞表面 具有针对基于合成免疫的靶向的项目定义的最佳属性的分子，以及 利用这一点来创造和认证基于高危儿童癌症临床前疗效的新疗法 模型项目2将重点关注免疫治疗耐药性的主要机制， 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将重点关注儿童和许多成人之间的主要区别 恶性肿瘤，儿科癌症通常引起很少的适应性免疫，并开发方法， 增强针对儿科癌症特异性抗原靶标的适应性免疫应答。拟议的中心 将发现和开发有效的免疫策略，将立即翻译为 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， 将促进高风险儿科恶性肿瘤的研究进展。