Clinical Vector for TCR Immunotherapy Targeted to Melanoma

描述（由申请人提供）：该II期提案是我们I期奖项“针对黑色素瘤的TCR免疫治疗慢病毒载体”的延续。“我们已经成功地实现了我们最初申请时设定的里程碑。我们产生了一个慢病毒基因载体，能够表达特异性的酪氨酸酶：368-376表位的T细胞受体（TCR），并证明了这种克隆的TCR在体外和体内模型的活性。用这种特异性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，女性第七大常见癌症。在这个提议中，我们将产生临床级TCR载体，即患者来源的T细胞，然后启动I期临床试验以评估该程序的安全性。NCI最近的研究结果表明，化疗引起的一过性淋巴细胞减少症对治疗效果至关重要。我们提出的试验将是第一次尝试在NCI范围之外进行这种手术，并将为医院环境中治疗黑色素瘤建立一个新的范例。其次，这笔赠款将推动表达这种TCR的慢病毒载体的产品开发，使其在产品开发的关键路径上又向前迈进了一步，并进一步推动Lentigen的关键企业目标，成为慢病毒载体技术临床应用的领导者。很明显，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治疗方法无法提供满意结果的肿瘤。慢病毒载体已在HIV/AIDS的I期试验中进行了评估。这项提案将是第一个使用慢病毒技术治疗黑色素瘤的提案。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，和2）用该载体转染患者T细胞并根据我们的I期FDA临床试验输注它们-设计用于评估转导的T细胞输注在淋巴细胞耗尽患者中的安全性。总之，Lentigen Corp.沿着Michael Nishimura博士和他在南卡罗来纳州医科大学的临床团队在临床环境中提供工程化人类T细胞的全面评价方面具有独特的优势，可以推广到治疗这种危及生命的恶性肿瘤的其他中心。 公共卫生相关性：该提案的目标是开发一种新的和改进的黑色素瘤免疫疗法，这种肿瘤目前的疗法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进行操作，并输回患者体内，以消除黑色素瘤肿瘤细胞。由于其为其他治疗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全球的黑色素瘤癌症患者和医疗保健提供者具有重要意义。

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.