Bench to Beside and Back translational immuno-onocology-Cures

四个CCR项目目前支持这个癌症登月板凳旁边和后面奖：1。TME为儿童肉瘤的NK细胞治疗提供了信息，由Rosandra Kaplan（CCR）和Timothy Cripe（全国儿童医院）领导。该项目的总体目标是开发具有TGF-β印迹的自然杀伤（NK）细胞疗法，其可以通过操纵免疫抑制性肿瘤微环境（TME）来增强，从而改善NK细胞介导的抗肿瘤免疫力，并作为复发性儿科肉瘤患者的潜在有效疗法。骨和软组织肉瘤是儿科、青少年/年轻成人（AYA）患者中最常见的实体瘤之一。尽管由于手术局部控制和多药化疗的进步而改善了预后，但复发性、转移性或难治性疾病患者的预后仍然很差。对于这些患者，迫切需要新的治疗方法。Nationwide Children's Hospital（NCH）的团队开发了一种基因修饰的饲养细胞系，其能够从各种来源广泛地离体繁殖高活性的人NK细胞，并且这种方法已经在血液恶性肿瘤和脑肿瘤的早期临床试验中进行了评估。2. Nitin罗珀（CCR）和John Maris（CHOP）领导的DLK 1定向免疫疗法靶向神经内分泌肿瘤。该项目的核心目标是发现和优先考虑儿童癌症的免疫靶点。表面受体δ样非典型Notch配体1（DLK 1）由于在许多儿童和成人神经内分泌（NE）肿瘤中的高表达但具有有限的正常表达而被优先作为靶点。基于证明新型DLK 1导向抗体-药物偶联物（ADCT-701）在神经母细胞瘤中的疗效的临床前数据，研究者团队提议研究患有NE肿瘤的成人和儿童患者，以进一步开发DLK 1导向免疫疗法。DLK 1在许多儿童和成人NE肿瘤中高表达的发现具有高度意义，因为神经内分泌肿瘤难以治疗并且需要新的治疗方法。DLK 1是神经母细胞瘤中未分化状态的关键介质，并且神经母细胞瘤在DLK 1的遗传缺失后终末分化。拟议的工作有可能导致增强对重要疾病过程的理解，并导致新的治疗干预。3. B2B和Back：儿童白血病的CD 22和CD 19/22 CAR免疫疗法，由Naomi Taylor（CCR）和Crystal Mackall（斯坦福大学）领导。Taylor和Mackall团队正在使用相同的CD 22和CD 19/CD 22二价CAR载体进行临床试验，但这两个研究中心使用不同的制造程序来产生输注到患者体内的CAR转导的T细胞。目前的建议是检验CAR-T细胞免疫潜力的变异性受制造平台变化的影响，并且可以通过评估抗原依赖性CAR-T细胞活性来预测的假设。这些参数的高通量分析将用于优化CAR制造，评估不同的患者结局，并增强儿科白血病患者的持久反应。4. Inotuzumab后CD 22的选择性剪接，由Nirali Shah（CCR）和Andrei Kazas-Tikhonenko（CHOP）领导。本项目旨在探索B-ALL肿瘤细胞中CD 22 mRNA剪接改变（缺失外显子2）导致CD 22蛋白表达缺失，从而导致这些肿瘤细胞对CD 22特异性免疫疗法产生获得性耐药性的机制。该项目是一个有吸引力的混合表征的临床样本从CD 22为基础的临床试验，并在体外加体内研究的调节CD 22剪接;在一起，这些研究可以确定新的治疗策略，迫使CD 22蛋白表达在B-ALL细胞和改善抗CD 22免疫治疗。

Four CCR projects are currently supported by this Cancer Moonshot Bench to Beside and Back award: 1. TME informed NK cell therapy for pediatric sarcomas, led by Rosandra Kaplan (CCR) and Timothy Cripe (Nationwide Children's Hospital). The overall goal of this project is to develop natural killer (NK) cell therapy with TGF-beta imprinting that can be augmented through manipulation of the immune suppres sive tumor microenvironment (TME) leading to improved NK cell-mediated anti-tumor immunity, and serves as a potential effective therapy for patients with relapsed pediatric sarcoma. Bone and soft tissue sarcomas are one of the most common solid tumors in pediatric, adolescent/young adult (AYA) patients. Despite improved outcomes due to advances in surgical local control and multi-agent chemotherapy, prog nosis for patients who develop recurrent, metastatic, or refractory disease remains poor. For these patients, new therapeutic approaches are urgently needed. The team at Nationwide Children's Hospital (NCH) has developed a genetically modified feeder cell line that enables extensive ex vivo propagation of highly-active human NK cells from various sources, and this methodology has been evaluated in early- phase clinical trials for hematologic malignancies and brain tumors. 2. Targeting neuroendocrine tumors with DLK1 directed immunother apy, led by Nitin Roper (CCR) and John Maris (CHOP). A central goal of this project is to discover and prioritize immunotherapeutic targets in childhood cancers. Surface receptor Delta Like Non-Canonical Notch Ligand 1 (DLK1) has been prioritized as a target due to the pro tein's high expression in many pediatric and adult neuroendocrine (NE) tumors but with restricted normal expression. Based on pre-clinical data demonstrating efficacy of a novel DLK1-directed antibody-drug conjugate (ADCT-701) in neuroblastoma, the investigator team pro poses to study adult and pediatric patients with NE tumors to further develop DLK1-directed immunotherapy. The discovery that DLK1 is hiqhly expressed in many pediatric and adult NE tumors is of high significance since neuroendocrine tumors are difficult to treat and novel therapeutics are needed. DLK1 is a key mediator of the undifferentiated state in neuroblastoma, and neuroblastomas terminally differenti ate upon genetic depletion of DLK1. The proposed work has the potential to result in enhanced understanding of an important disease process and lead to a new therapeutic intervention. 3. B2B and Back: CD22 and CD19/22 CAR immunotherapies for childhood leukemia, led by Naomi Taylor (CCR) and Crystal Mackall (Stanford). The Taylor and Mackall teams are carrying out clinical trials with identical CD22 and CD19/CD22-bivalent CAR vectors but the two sites are using different manufacturing procedures to generate the CAR-transduced T cells that are being infused into patients. The current proposal is to test the hypothesis that variability in CAR-T cell immunotherapeutic po tential is affected by variations in manufacturing platforms and can be predicted through evaluation of antigen-dependent CAR-T cell activ ity. High throughput analyses of these parameters will be leveraged to optimize CAR manufacturing, evaluate divergent patient outcomes, and enhance durable responses in pediatric leukemia patients. 4. Alternative splicing of CD22 following Inotuzumab, led by Nirali Shah (CCR) and Andrei Thomas-Tikhonenko (CHOP). This project is designed to explore the mechanism(s) by which altered splicing of CD22 mRNA, to delete Exon 2, leads to loss of CD22 protein expression in B-ALL tumor cells, and thus leads to the acquired resistance of those tumor cells to CD22-specific immunotherapies. The project is an attractive blend of characterization of clinical samples from CD22-based clinical trials, and in vitro plus in vivo studies of the regulation of CD22 splicing; together, these studies could identify new therapeutic strategies to force CD22 protein expression in B-ALL cells and improve anti-CD22-immunotherapy.