ChNKG2D-Targeted Cellular Cancer Therapy: Phase I Clinical Trial

ChNKG2D 靶向细胞癌症治疗：I 期临床试验

基本信息

批准号：
8394167
负责人：
MICHAEL W FANGER
金额：
$ 139.99万
依托单位：
CELDARA MEDICAL, LLC
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-09 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8394167
关键词：
Animal Model Antibodies Antigen Receptors Biological Assay Biological Markers CD3 Antigens Cancer Burden Cancerous Caring Cause of Death Cells Clinic Clinical Clinical Protocols Clinical Trials Cryopreservation Data Development Disease Dose Drug Kinetics Future Gases Grant Human Immune Immune response Immune system Immunity Incidence Institutional Review Boards Investments Lead Ligands Liquid substance Lymphoma Malignant Neoplasms Malignant neoplasm of ovary Methods Modeling Multiple Myeloma Mus Neoplasm Metastasis Normal tissue morphology Outcome Measure Patient Education Patients Phase Phase I Clinical Trials Phase II Clinical Trials Preparation Prevention Production Protocols documentation Qualifying Receptor Signaling Relapse Safety Serum-Free Culture Media Small Business Innovation Research Grant Solid Solid Neoplasm Specificity T cell therapy T-Lymphocyte Touch sensation Toxic effect Tumor Antigens Variant Work Writing base cancer therapy cancer type cell bank cell type cellular targeting commercialization design falls flasks in vivo innovation insight killings meetings neoplastic cell novel pre-clinical prevent primary outcome receptor tumor vector

项目摘要

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.

描述（由申请人提供）： 1975 年至 2000 年间，全球癌症负担翻了一番。2010 年，癌症成为全球主要死亡原因，预计到 2020 年将再次翻一番，到 2030 年将增加两倍。这种可怕的疾病已经影响到每个人尽管在预防和治疗方面投入巨资，但其影响仍在继续加速。理想情况下，任何癌症治疗都应该是有效的（杀死癌细胞）、有针对性的（即选择性的，以避免杀死健康细胞）和永久性的（避免复发和转移）。当今大多数癌症的护理标准都达不到部分或全部这些标准。我们开发了一种新疗法（chNKG2D T 细胞），通过使用宿主自身的免疫细胞，该疗法在动物模型中达到了这些标准。患者的 T 细胞经过修饰以表达嵌合 NKG2D (chNKG2D) 受体，进行扩增，然后返回患者体内。我们相信这一创新将带来一类具有巨大潜力的新型疗法，我们正在积极开发它用于治疗多种肿瘤，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、淋巴瘤和卵巢癌小鼠模型中实现 100% 存活和 100% 持久抵抗肿瘤再攻击的能力，建立了单剂量和多剂量的 MTD，确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，制定了在无血清培养基中扩增的方案，设计并测序了人类载体，在标准烧瓶和透气烧瓶中扩增了人类细胞，与以下人员进行了 IND 前会议FDA 撰写了超过 80% 的 IRB、RAC 和 IND 文件，并聘请了世界一流的临床团队。这笔资金将把 chNKG2D T 细胞带入临床，如果成功的话，将为 II 期临床试验做好准备。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 PG13 包装细胞中的 pSFG-chNKG2D 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准备工作：生成 chNKG2D 抗体和用于 PKPD 研究的 qPCR 测定，开发chNKG2D T 细胞临床规模生产和定义临床 SOP 的方案，以及确定与 chNKG2D T 细胞毒性及其体内存活相关的机制。在这笔拨款的第二年，我们将进行 I 期临床试验，招募患有液体和实体瘤的患者，并进行剂量递增以确定毒性和 MTD，并进一步了解作用机制。公共健康相关性：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进行同样的操作（例如预防转移性疾病）。该项目将最终对这种有前景的疗法进行临床试验。