Universal MUC1 Targeted Immunotherapy

通用MUC1靶向免疫疗法

• 批准号: 7743951
• 负责人: RIMAS J ORENTAS
• 金额: $ 14.07万
• 依托单位: LENTIGEN CORPORATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7743951
• 关键词: Activated Lymphocyte; Adenocarcinoma; Adoptive Immunotherapy; Adult; Animals; Antibodies; Antigen Presentation; Antigen Receptors; Antigen-Presenting Cells; Antineoplastic Agents; Avidity; Back; Binding; Biological; Biological Assay; Breast; CA-15-3 Antigen; CD19 gene; CD28 gene; CD3 Antigens; Cancer Burden; Cancer Patient; Carcinoma; Cell Death; Cells; Clinical; Clinical Investigator; Clinical Trials; Clonal Expansion; Data; Development; Effector Cell; Elements; Engineering; Evaluation; Exhibits; Future; Generations; Genes; Goals; Haplotypes; Head and Neck Cancer; Head and neck structure; Health Personnel; Human; Immune; Immune Cell Activation; Immune Targeting; Immunotherapy; In Vitro; Infusion procedures; Intellectual Property; Interleukin-2; Joints; Laboratories; Lentivirus Vector; Link; Lung; Lymphocyte; Lymphoma; MHC binding peptide; Malignant Neoplasms; Malignant neoplasm of lung; Memory; Methods; Modeling; Molecular Cloning; Mucin-1 Staining Method; Mus; Natural Killer Cells; Normal Cell; Patients; Peripheral Blood Mononuclear Cell; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Plasmids; Population; Pre-Clinical Model; Production; Prostate; Protocols documentation; Publications; Reagent; Relapse; Research; Research Proposals; Safety; Series; Signal Transduction; Small Business Innovation Research Grant; Staging; Structure; Subfamily lentivirinae; Surface; System; T-Cell Receptor; T-Lymphocyte; Techniques; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Therapeutic antibodies; Therapy Clinical Trials; Time; Translations; Transplantation; Treatment Efficacy; Tumor Antigens; United States; Universities; Vertebral column; Xenograft Model; Zidovudine; advanced disease; antigen processing; base; cancer cell; cancer therapy; cell suicide; cell type; cellular transduction; clinical efficacy; clinical toxicology; clinically relevant; design; effective therapy; immune function; improved; in vitro testing; in vivo; innovation; killings; medical schools; melanoma; mouse model; neoplastic cell; novel; novel strategies; novel therapeutics; pre-clinical; prevent; programs; public health relevance; receptor; receptor binding; success; suicide gene; therapy design; transduction efficiency; transgene expression; tumor; tumor growth; tumor xenograft; vector; willingness

DESCRIPTION (provided by applicant): The goal of this proposal is to evaluate lentiviral gene vectors expressing a novel T cell receptor (TCR), that binds directly to MUC1 on the surface of cancer cells, as a new therapeutic agent for the treatment of adult carcinoma. The TCR, the lentiviral vector used to induce its expression in transduced immune cells, and the target itself are unique with respect to the standard means by which adoptive immunotherapy is proposed for treating cancer. The MUC1-specific TCR identified by Dr. Olivera Finn recognizes a unique antigenic structure on hyopglycosylated MUC1 (found on 85% of all carcinomas but not on normal cells; including breast, prostate, head and neck, and lung cancer) as opposed to a peptide bound by MHC. This makes our TCR a truly universal reagent that is not dependent on MHC-restricted antigen presentation by the tumor. We will create a single chain "third-generation" vector that will express a chimeric antigen receptor (CAR) containing CD28, CD137 (4-1BB) and CD3-zeta chain signaling elements. These vectors will be evaluated in both T cells and NK cells. The vector system used will be Lentigen's proprietary backbone construct that includes the latest safety elements as well as additional selection markers such as the tmpk "suicide" gene. The target, hypoglycosylated MUC1, is well-established as a unique antigenic signature of cancer and is an ideal target for immune cells expressing a CAR. In this proposal we will test the central hypothesis that lentiviral engineered T cells with significant anti-tumor efficacy can be created by developing improved "third generation" chimeric antigen receptors (CAR) that will target and specifically kill MUC1+ cancers. These CAR-expressing cells will undergo the same mechanism of clonal expansion into effector and memory populations that occurs during conventional TCR-pepMHC interactions. Moreover we will also test a corollary hypothesis that NK cells transduced with CAR will also serve as potent anti-MUC1+ effector cells. Through our detailed analysis of the native TCR, first generation CAR, third generation CAR, and different ways of activating immune cells for lentiviral transduction and subsequent evaluation of effector function, we will create a definitive product, with a consistent means of implementing its use that is translatable to the clinical setting. We will evaluate both standard means of immune cell activation (IL-2 plus anti-CD3), newer generation methods (anti-CD3/anti- CD28 beads), and cutting edges techniques (cell based artificial antigen-presenting cells that also include CD137 signaling). We anticipate that the results generated in this proposal will serve as the basis for Phase II SBIR studies, during which we will test the ability of T cells or T cells +NK cells expressing CAR to control or eliminate tumor growth in a Phase I clinical trial. The lentiviral production capability of Lentigen Corp., combined with the translational MUC1 research by Dr. Olivera Finn at the University of Pittsburgh makes this a realistic first step in carrying out clinical trials. These trials will be the first to evaluate non-MHC restricted TCR activity that will benefit patients suffering from MUC1+ cancer. PUBLIC HEALTH RELEVANCE: The goal of this research proposal is to develop a new anti-cancer agent that will benefit patients for which we currently do not have effective therapy. This therapy is based on the activation of immune cells outside the body, giving activated immune cells a new receptor on their surface that recognizes cancer cells, and then introducing these cells back into the body. We anticipate these modified cells will eliminate cancer cells upon re-infusion and benefit patients failing other therapies. This therapy, if proved successful, will have a significant impact for cancer patients and healthcare providers designing therapy for them in the United States and worldwide.

描述（由申请人提供）：该提案的目的是评估表达新型T细胞受体（TCR）的慢病毒基因载体，该基因在癌细胞表面直接与MUC1结合，作为用于治疗成人癌症的新治疗剂。 TCR，用于诱导其在转导的免疫细胞中表达的TCR，靶病毒载体，对于提出过继免疫疗法治疗癌症的标准手段，靶标本身是独一无二的。 Olivera Finn博士鉴定的MUC1特异性TCR识别出在氢化糖基化的MUC1上的独特抗原结构（在所有癌的85％，但在正常细胞中发现，包括乳腺，前列腺，头颈和肺癌在内），与MHC的肽限制了。这使我们的TCR成为真正的通用试剂，不依赖于肿瘤的MHC限制抗原表现。我们将创建一个单链“第三代”载体，该载体将表达包含CD28，CD137（4-1BB）和CD3-Zeta链信号元素的嵌合抗原受体（CAR）。这些载体将在T细胞和NK细胞中进行评估。使用的向量系统将是Lentigen的专有骨干构建体，其中包括最新的安全元素以及其他选择标记，例如TMPK“自杀”基因。降低糖基化的MUC1的靶标是癌症的独特抗原特征，是表达汽车的免疫细胞的理想靶标。在此提案中，我们将通过开发改进的“第三代”嵌合抗原受体（CAR）来测试中心假设，即具有显着抗肿瘤功效的慢病毒工程T细胞可以产生，该嵌合抗原受体（CAR）将靶向并特别杀死MUC1+癌症。这些表达汽车的细胞将经历在常规TCR-PEPMHC相互作用期间发生的克隆扩张和记忆群相同的机制。此外，我们还将检验一个推论假设，即用CAR转导的NK细胞也将作为有效的抗MUC1+效应细胞。通过我们对天然TCR，第一代汽车，第三辆车的详细分析以及激活免疫细胞进行慢病毒转导的不同方法，以及随后对效应子功能的评估，我们将创建一个确定的产品，并具有一致的实施其用途的方法，可将其用于临床环境转换为临床环境。我们将评估免疫细胞激活的标准平均值（IL-2 Plus抗CD3），较新的生成方法（抗CD3/抗CD28珠）和切割边缘技术（基于细胞的基于细胞的人工抗原呈递细胞），这些细胞也包括CD137信号）。我们预计，该提案中产生的结果将成为II期SBIR研究的基础，在此期间，我们将测试T细胞或T细胞 +NK细胞在I期临床试验中控制或消除CAR来控制或消除肿瘤生长的能力。 Lentigen Corp.的慢病毒生产能力，再加上匹兹堡大学Olivera Finn博士的翻译MUC1研究，这是进行临床试验的现实第一步。这些试验将是第一个评估非MHC限制的TCR活性的试验，这将使患有MUC1+癌症患者的患者受益。 公共卫生相关性：这项研究建议的目标是开发一种新的抗癌剂，该毒剂将使我们目前没有有效治疗的患者受益。该疗法基于体外外部的免疫细胞的激活，使活化的免疫细胞在其表面上是识别癌细胞的新受体，然后将这些细胞引入体内。我们预计这些修饰的细胞将在再灌注后消除癌细胞，并使其他疗法失败的患者受益。如果证明成功，这种疗法将对癌症患者和医疗保健提供者在美国和全球为他们设计疗法的医疗保健提供者产生重大影响。