Clinical Vector for TCR Immunotherapy Targeted to Melanoma

描述（由申请人提供）：该II期申请是我们I期奖项“针对黑色素瘤的TCR免疫治疗的慢病毒载体”的延续。我们已经成功地实现了最初应用程序中设定的里程碑。我们生成了一个慢病毒基因载体，能够表达酪氨酸酶368-376表位特异性T细胞受体（TCR），并在体外和体内模型中证明了该克隆TCR的活性。通过这种特异性TCR转导的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，黑色素瘤目前是美国男性第六大常见癌症，美国女性第七大常见癌症。在这项提议中，我们将生成临床级TCR载体，转导患者来源的T细胞，然后启动I期临床试验来评估该程序的安全性。NCI最近的研究结果表明，化疗引起的短暂性淋巴细胞减少对治疗效果至关重要。我们建议的试验将是第一个在NCI范围之外尝试这种方法的试验，并将为医院环境中治疗黑色素瘤建立一个新的范例。其次，这笔资金将使表达该TCR的慢病毒载体的产品开发在产品开发的关键路径上又向前迈进了一步，并进一步实现Lentigen成为慢病毒载体技术临床应用领导者的关键公司目标。很明显，免疫疗法将是有效控制黑色素瘤的一个关键特征，目前的治疗方法并不能提供令人满意的结果。慢病毒载体已在艾滋病毒/艾滋病的一期试验中进行了评估。这将是第一个使用慢病毒技术治疗黑色素瘤的提议。我们的里程碑将是1)生成GMP级慢病毒载体，建立临床使用的释放标准，2)根据我们的I期FDA临床试验，用该载体转导患者T细胞并输注它们，旨在评估转导T细胞输注淋巴衰竭患者的安全性。总之，Lentigen Corp.与南卡罗来纳医科大学的Michael Nishimura博士及其临床团队在提供工程人类T细胞临床环境的综合评估方面具有独特的优势，可以推广到其他中心治疗这种危及生命的恶性肿瘤。

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.