CORE SUPPORT FOR THE IMMUNE CELL NETWORK

近年来，用于临床应用的自体或同种异体细胞的工程化进程加快，在治疗癌症以及放射和化疗造成的组织损伤方面取得了重大成功。可以利用许多细胞类型，包括造血干细胞、诱导多能干细胞(IPSC)、淋巴细胞、树突状细胞、间充质干细胞等。 以细胞为基础的免疫疗法尤其成功。目前已批准用于治疗白血病、淋巴瘤和骨髓瘤等恶性血液病的药物；治疗实体肿瘤的工作也很有希望。然而，将这一强大的治疗策略广泛、有效地应用于临床仍然存在重大的科学、技术、临床和监管挑战。研究人员刚刚开始开发在有效摧毁肿瘤的同时保留正常组织的结构。技术挑战包括使用独特的患者特定的起始材料或不会引发免疫排斥的同种异体产品来制造患者特定的最终产品的复杂制造过程。必须开发标准化的分析方法，以便在给患者使用这些“活药物”之前和之后对细胞产品进行充分的表征，而动物模型研究可能无法预测。此外，许多治疗适应症是针对罕见癌症或那些患者人数较少的亚型，因此不可能在单一临床地点产生具有统计意义的试验对象。随着细胞治疗科学的进步，监管科学也必须有相关的进步，以确保质量和安全都符合最高标准。目前，还没有一家机构有能力解决细胞治疗领域存在的所有障碍。 NCI寻求为免疫细胞网络(ICN)的成员提供核心支持。ICN将由NIH资助的中心组成，这些中心促进新发现，支持跨科学、临床和监管学科的强有力的合作，并在整个网络中提供自己的资源，以促进在cGMP条件下生产的细胞疗法的临床试验应用。每个中心将使用采用细胞疗法的方法对一种或多种癌症进行研究。这项研究包括选择特定癌症的认证靶点，询问治疗机制(S)，确定治疗细胞的适合性和持久性，以及在新型细胞治疗产品的人体试验中评估临床疗效。支持的特定细胞疗法可能包括免疫疗法[嵌合抗原受体(CAR)T细胞、肿瘤浸润性淋巴细胞(TIL)、工程T细胞受体(TCR)-T细胞、自然杀伤(NK)、树突状细胞(DC)和巨噬细胞(MΦ)]；干细胞疗法(工程IPSC、组织干细胞、造血祖细胞)；以及旁分泌作用细胞(工程间充质细胞)。这些中心将在现场为自己的试点试验制造细胞治疗产品，并在多地点临床研究中进行科学合作，以迅速提出最具创新性的想法。

The engineering of autologous or allogenic cells for clinical application has accelerated in recent years, to a point where significant successes have been observed with treatments for cancer and tissue damage from radiation and chemotherapy. Many cell types may be utilized including hematopoietic stem cells, induced pluripotent stem cells (iPSC), lymphocytes, dendritic cells, mesenchymal stem cells, and others. Cell-based immunotherapies have been particularly successful. There are approved agents for hematologic malignancies such as leukemia, lymphoma and myeloma; promising work is also being conducted to treat solid tumors. However, there remain significant scientific, technical, clinical, and regulatory challenges to bringing this powerful therapeutic strategy into widespread, effective clinical use. Investigators are just beginning to develop constructs that effectively destroy tumors while preserving normal tissue. Technical challenges include the complex manufacturing process used to make patient-specific final products from unique patient-specific starting materials or allogenic products that do not trigger an immune rejection. Standardized analytical assays must be developed to fully characterize cell products before and after these ‘living drugs’ are administered to patients and animal model studies may not be predictive. Furthermore, many therapeutic indications are for rare cancers or for those subtypes with small number of patients making it impossible to accrue statistically significant trial subjects at a single clinical site. As cell therapy science advances, there must also be an associated advancement in regulatory science to ensure that both quality and safety conform to the highest standards. Currently, no single institution is equipped to address all the hurdles that exist in the cell therapy field. The NCI seeks to provide core support for members of an Immune Cell Network (ICN). The ICN will consist of NIH-funded Centers that foster new discoveries, support strong collaborations across scientific, clinical, and regulatory disciplines, and make their own resources available across the network to advance the application of cell therapies produced under cGMP conditions for clinical trials. Each center will conduct research on one or more cancers using an adoptive cell therapy approach. The research consists of selecting a credentialed target for a specific cancer, interrogating therapeutic mechanism(s) of action, determining therapeutic cell fitness and persistence, and assessing clinical efficacy in human trials of novel cell therapy products. Specific cellular therapies supported may include immunotherapies [chimeric antigen receptor (CAR) T-cells, tumor-infiltrating lymphocytes (TIL), engineered T cell receptor (TCR)-T cells, natural killer (NK), dendritic cell (DC), and macrophage (MΦ)]; stem cell therapies (engineered iPSC, tissue stem cells, hematopoietic progenitors); and paracrine-acting cells (engineered mesenchymal cells). The centers will manufacture cell therapy products onsite for their own pilot trials and collaborate scientifically in multisite clinical studies to bring forward the most innovative ideas rapidly.