ChNKG2D-Targeted Cellular Cancer Therapy: Phase I Clinical Trial

描述（由申请人提供）：1975年至2000年期间，全球癌症负担翻了一番。2010年，癌症成为全世界死亡的主要原因，预计到2020年将再翻一番，到2030年将翻三倍。这一可怕的疾病影响到我们每个人，尽管在预防和治疗方面投入了大量资金，但其影响继续加速。理想情况下，任何癌症治疗都应该是有效的（杀死癌细胞），靶向的（即选择性的，以避免杀死健康细胞）和永久性的（以避免复发和转移）。今天对大多数癌症的护理标准在这些标准中的一些或全部方面都不合格。我们开发了一种新的疗法（chNKG 2D T细胞），通过使用宿主自身的免疫细胞，在动物模型中达到了这些标志。患者的T细胞被修饰以表达嵌合NKG 2D（chNKG 2D）受体，扩增，然后返回患者。我们相信，这项创新将带来一种具有巨大潜力的新疗法，我们正在积极开发用于治疗多种肿瘤，包括骨髓瘤，淋巴瘤和卵巢癌。迄今为止，我们已经：证明了在多发性骨髓瘤、淋巴瘤和卵巢癌的鼠模型中实现100%存活和100%持久保护对抗肿瘤再激发的能力，建立了单剂量和多剂量的MTD，鉴定了用于临床的生物标志物，证明了冷冻保存后的等效功能，开发了在无血清培养基中扩增的方案，设计并测序了人载体，在标准和透气烧瓶中扩增人细胞，与FDA进行了IND前会议，撰写了>80%的IRB，RAC和IND文件，并聘请了世界一流的临床团队。这项资助将使chNKG 2D T细胞进入临床，如果成功的话，将产生一种为II期临床试验做好准备的疗法。在此，我们建议完成剩余的临床前开发并进行I期临床试验。我们将使用PG 13包装细胞中的pSFG-chNKG 2D以及>9升GMP/临床级载体生产并鉴定主细胞库，通过以下方式完成临床试验制备：生成针对chNKG 2D的抗体和用于PKPD研究的qPCR检测试剂盒，制定临床规模生产chNKG 2D T细胞的方案并定义临床SOP，和确定与chNKG 2D T细胞的毒性及其体内存活相关的机制。在第二年，我们将进行I期临床试验，招募液体和实体肿瘤患者，并进行剂量递增以确定毒性和MTD，并进一步了解作用机制。 公共卫生相关性：2010年，癌症超过心血管疾病，成为全球头号杀手。通过去除、纯化、修饰、生长，然后注入患者的免疫细胞，我们已经能够靶向并杀死液体和固体癌症，并同时训练患者自身的免疫系统也这样做（例如预防转移性疾病）。该项目将最终在临床试验这种有前途的疗法。

DESCRIPTION (provided by applicant): The global burden of cancer doubled between 1975 and 2000. Cancer became the leading cause of death worldwide in 2010, and is projected to double again by 2020 and to triple by 2030. This horrible disease has touched each of us, and despite enormous investments in prevention and treatment, its impact continues to accelerate. Ideally, any cancer therapy should be effective (at killing cancerous cells), targeted (i.e. selective, to avoid killing healthy cells), and permanent (to avoid relapse and metastasis). Today's standards of care for most cancers fall short in some or all of these criteria. We have developed a novel therapy (chNKG2D T cells) that has met these marks in animal models through the use of the host's own immune cells. A patient's T-cells are modified to express chimeric NKG2D (chNKG2D) receptors, expanded, and then returned to the patient. We believe that this innovation will lead to a new class of therapies with remarkable potential, and we are actively developing it for therapy of several tumors including myeloma, lymphoma, and ovarian cancer. To date we have: demonstrated the ability to achieve 100% survival and 100% durable protection against tumor rechallenge in murine models of multiple myeloma, lymphoma, and ovarian cancer, established the MTD for single and multiple doses, identified biomarkers for use in the clinic, demonstrated equivalent function post- cryopreservation, developed protocols for expansion in serum-free media, designed and sequenced the human vector, expanded human cells in standard and gas permeable flasks, conducted a pre-IND meeting with FDA, written >80% of the IRB, RAC, and IND documents, and engaged a world-class clinical team. This grant will take chNKG2D T cells into the clinic, and if successful will yield a therapy ready for Phase II clinical trials. Herein we propose to complete the remaining preclinical development and conduct a Phase I clinical trial. We will produce and qualify a master cell bank using pSFG-chNKG2D in PG13 packaging cells as well as >9 liters of GMP/clinical grade vector, complete clinical trial preparations by: Generating an antibody to chNKG2D and a qPCR assay for PKPD studies, Developing protocols for clinical scale production of chNKG2D T cells and defining clinical SOPs, and Determining mechanisms associated with toxicity of chNKG2D T cells and their survival in vivo. In Year Two of this grant we will conduct a Phase I clinical trial, enrollig patients with both liquid and solid tumors and conducting a dose escalation to determine toxicity and MTD, and gain further insight into mechanism of action. PUBLIC HEALTH RELEVANCE: In 2010 cancer surpassed CVD as the leading killer worldwide. By removing, purifying, modifying, growing, then infusing a patient's immune cells, we have been able to target and kill both liquid and solid cancers, and to simultaneously train the patient's own immune system to do likewise (e.g. to prevent metastatic disease). This project will culminate in a clinical trial of this promising therapy.