Clinical Vector for TCR Immunotherapy Targeted to Melanoma

描述(申请人提供)：这个第二阶段的提案是我们第一阶段奖项的延续，“针对黑色素瘤的TCR免疫治疗的慢病毒载体。”我们已经成功地实现了最初应用中设定的里程碑。我们构建了能够表达酪氨酸酶368-376表位的T细胞受体(TCR)的慢病毒基因载体，并在体外和体内模型中证明了该克隆的TCR的活性。通过转导这种特定TCR的T细胞靶向黑色素瘤相关分化抗原将为黑色素瘤患者创造一种新的治疗选择。根据美国癌症协会的数据，黑色素瘤目前在男性中排名第六，在美国女性中排名第七。在这项建议中，我们将产生临床级TCR载体，转导患者来源的T细胞，然后启动I期临床试验，以评估该程序的安全性。NCI的最新发现表明，化疗引起的一过性淋巴细胞减少是治疗效果的关键。我们提议的试验将是第一次在NCI的范围外尝试这一程序，并将建立一个在医院环境下治疗黑色素瘤的新范例。其次，这笔赠款将推动表达该TCR的慢病毒载体的产品开发在产品开发的关键道路上向前迈进一步，并进一步推动Lentigen成为慢病毒载体技术临床应用的领先者的关键公司目标。显然，免疫治疗将是有效控制黑色素瘤的关键特征，黑色素瘤是一种目前的治疗方法不能提供令人满意的结果的肿瘤。慢病毒载体已经在艾滋病毒/艾滋病的第一阶段试验中进行了评估。这项提案将是第一个使用慢病毒技术治疗黑色素瘤的方案。我们的里程碑将是1)产生GMP级慢病毒载体，建立临床使用的释放标准，以及2)用该载体转导患者T细胞并根据我们FDA的I期临床试验输注它们，该临床试验旨在评估转导T细胞输注在淋巴枯竭患者中的安全性。总之，Lentigen公司与南卡罗来纳医科大学的Michael Nishimura博士和他的临床团队处于独特的地位，可以在临床环境中提供对工程人类T细胞的全面评估，这种评估可以推广到其他治疗这种威胁生命的恶性肿瘤的中心。 公共卫生相关性：这项提案的目标是开发一种新的、改进的黑色素瘤免疫疗法，目前的治疗方法对这种肿瘤并不能提供令人满意的结果。这种疗法的特点是激活免疫细胞，这些细胞将在实验室中被操纵并回输给患者，以消除黑色素瘤肿瘤细胞。由于其为那些其他疗法失败的患者提供解决方案的巨大潜力，这种疗法将对美国和世界各地的黑色素瘤癌症患者和医疗保健提供者具有重大意义。

DESCRIPTION (provided by applicant): This Phase II proposal is a continuation of our Phase I award, "Lentiviral Vectors for TCR Immunotherapy Targeted to Melanoma." We have successfully achieved the milestones laid out in our initial application. We generated a lentiviral gene vector capable of expressing a T cell receptor (TCR) specific for the tyrosinase:368-376 epitope, and demonstrated the activity of this cloned TCR in in vitro and in vivo models. The targeting of the melanoma-associated differentiation antigen by T cells transduced with this specific TCR will create a new therapeutic option for patients with melanoma. According to the American Cancer Society melanoma is currently the sixth most common cancer in men and the seventh most common cancer in American women. In this proposal we will generate clinical grade TCR vector, transduce patient-derived T cells, and then initiate a phase I clinical trial to evaluate the safety of this procedure. Recent findings from the NCI indicate that a transient lymphopenia induced by chemotherapy is essential for therapeutic effect. The trial we propose will be the first to try this procedure outside of the confines of the NCI, and will establish a new paradigm for the treatment of melanoma in the hospital setting. Secondarily this grant will move product development for the lentiviral vector expressing this TCR another step forward in the critical path of product development, and further key corporate goals of Lentigen to become the leader in clinical application of lentiviral vector technology. It is clear that immunotherapy will be a key feature for effective control of melanoma, a type of tumor for which current therapies do not offer satisfactory results. Lentiviral vectors have been evaluated in Phase I trials in HIV/AIDS. This proposal will be the first to use lentiviral technology in the treatment of melanoma. Our milestones will be 1) To generate GMP grade lentiviral vector, establishing release criteria for clinical use, and 2) to transduce patient T cells with this vector and infuse them according to our phase I FDA clinical trial- designed to evaluate the safety of transduced T cell infusion in lymphodepleted patients. In summary, Lentigen Corp. along with Dr. Michael Nishimura and his clinical team at the Medical University of South Carolina are uniquely positioned to provide a comprehensive evaluation of engineered human T cells in a clinical setting that can be generalized to other centers treating this life-threatening malignancy. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to develop a novel and improved immunotherapy for melanoma, a tumor for which current therapies do not offer satisfactory results. This therapy will feature the activation of immune cells that will be manipulated in the laboratory and infused back into the patient in order to eliminate melanoma tumor cells. Because of its great potential to offer a solution for those patients failing other therapies, this therapy will have significant relevance for cancer patients with melanoma and health care providers in the United States and worldwide.