Engaging and Enhancing Neuroblastoma Immune Targeting

总体摘要/摘要 儿童癌症研究领域面临着一个重大的悖论。几十年前， 专注于癌症儿童的先驱调查人员领导了一场革命，导致了以前无法治愈的 恶性肿瘤变得可以治愈。相比之下，在过去的二十年里，基础科学继续 提高对儿童癌症发生的基本认识，但大多数儿童癌症的治愈率 恶性肿瘤已经停滞不前，这一领域已经亲眼目睹了当前的标准疗法通常 让幸存者背负着威胁生命的治疗引发的疾病。令人警醒的是，对于大多数儿童来说， 复发，几乎没有新的治疗选择，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资金机会 该倡议通过形成儿科免疫疗法的发现和发展直接解决了这一悖论 网络(PI-DDN)。CD19指导下的B-ALL和神经母细胞瘤的免疫治疗现已获得许可 免疫疗法在高度难治的淋巴系统恶性肿瘤病例中表现出前所未有的活性。这个 菲尔德现在准备进行集中和持续的多学科努力，以扩大这些早期的成功，以及 从总体上重新思考我们对儿童癌症治疗的方法。在这里，我们提出一种儿科免疫肿瘤学 儿童最佳免疫治疗策略的发现和发展中心 癌症。我们设想该中心将为PI-DDN提供一个中心枢纽，为 多学科研究，共同目标是为儿童创造新的癌症免疫疗法。这 中心包含三个高度集成的多机构项目，由一个行政和 统计核心。这里要检验的最重要的假设是，儿童癌症具有特定的家族特征。 合理、有效地靶向肿瘤发生和免疫逃逸的机制 设计和开发了免疫治疗方案。项目1将发现特定血统的细胞表面 具有项目定义的基于合成免疫治疗靶向的最佳属性的分子，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 模特们。项目2将重点研究免疫疗法耐药的主要机制，方法是开发 避免肿瘤内和肿瘤间的异质性以及由两者引起的T细胞功能障碍的根本问题 内在因素和外在因素。项目3将侧重于儿童和许多成人之间的主要区别 恶性肿瘤，与儿童癌症通常引起的获得性免疫很少，并开发方法 增强针对儿科癌症特异性抗原靶点的适应性免疫反应。拟建的中心 将发现和开发有效的免疫治疗策略，这些策略将立即转化为 临床，旨在对儿童癌症预后产生重大直接影响，作为PI-DDN的一部分 将催化跨高危儿科恶性肿瘤的研究进展。

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.