Lentiviral Vectors for TCR Immunotherapy Targeted to melanoma

描述（由申请人提供）：项目总结/摘要：本提案的总体目标是评价新概念是否使用表达能够识别酪氨酸酶：368-376表位的高亲和力T细胞受体（TCR）的慢病毒工程化T细胞（一种黑色素瘤/黑色素细胞分化肿瘤相关抗原）改善黑色素瘤免疫治疗的疗效。根据美国癌症协会，黑色素瘤目前是美国男性中第六常见的癌症，在美国女性中第七常见。在这项提案中，我们将测试基本假设，即可以通过使用慢病毒载体技术创建对黑色素瘤具有重定向特异性的人类T细胞，并可以提供临床相关和成功的治疗方法。最终目标是开发一种新的和改进的黑色素瘤治疗方法，这种肿瘤的目前治疗方法不能提供令人满意的结果。慢病毒载体（LV）已在HIV/AIDS患者的I期临床试验中成功评估，提供了更广泛地将该技术应用于治疗其他疾病（特别是癌症）的可能性。Lentigen的合作者Michael Nishimura博士帮助开拓了过继免疫疗法，作为黑色素瘤的潜在治疗方法。因此，在该提议的目的1中，我们将开发表达能够识别酪氨酸酶：368-376表位的TCR的a和B链的自失活（SIN）LV。在目标2中，我们将与Nishimura博士的团队一起测试LV-TCR转导的T细胞在体内预防黑色素瘤肿瘤生长和治疗已建立肿瘤的安全性和有效性。我们将进行2种一般类型的实验，以测试在工程化的人T细胞中表达的我们的慢病毒载体的体内功效和植入潜力。总之，Lentigen Corp.和Nishimura博士的实验室具有独特的优势，可以提供对重定向T细胞方法的首次全面评估，以在黑色素瘤患者中产生抗肿瘤作用，并将其应用于未来的临床试验，用于这种危及生命的恶性肿瘤患者。项目叙述：该提案的最终目标是开发一种用于黑色素瘤的新型和改进的免疫疗法，目前的疗法不能提供令人满意的结果。这种疗法是基于免疫细胞的激活，这些细胞将在实验室中进行操作，并放回患者体内以对抗黑色素瘤肿瘤细胞。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): Project Summary/Abstract: The overall goal of this proposal is to evaluate the novel concept whether using lentiviral-engineered T cells that express high affinity T cell receptor (TCR) capable of recognizing the tyrosinase:368-376 epitope, a melanoma/melanocytes differentiation tumor associated antigen have improved efficacy for melanoma immunotherapy. According to the American Cancer Society melanoma is currently the 6th most common cancer in American men and the 7th most common in American women. In this proposal, we will test the fundamental hypothesis that human T cells with redirected specificity for melanoma can be created by using lentiviral vector technology and can offer a clinically relevant and successful therapeutic approach. The ultimate goal is the development of a novel and improved therapy for melanoma, a type of tumor for which the current therapies do not offer satisfactory results. Lentiviral vectors (LVs) have been successfully evaluated in Phase l clinical trials in patients with HIV/AIDS, offering the possibility to more broadly apply this technology for the treatment of other diseases, particularly cancer. Lentigen's collaborator Dr. Michael Nishimura has helped pioneer adoptive immunotherapy as a potential therapeutic approach for melanoma. Therefore, in Aim 1 of this proposal, we will develop self inactivating (SIN) LVs expressing a and B chains of the TCR capable of recognizing the tyrosinase: 368-376 epitope. In Aim 2, together with Dr. Nishimura's team, we will test safety and efficacy of LV-TCR transduced T cells in preventing melanoma tumor growth and treating established tumors in vivo. We will carry out 2 general types of experiments in order to test the in vivo efficacy and engraftment potential of our lentiviral vectors expressed in engineered human T cells. In summary, Lentigen Corp. and Dr. Nishimura's laboratory are uniquely positioned to provide the first comprehensive evaluation of the redirected T cell approach to generate anti-tumor effects in melanoma patients and to apply this in a future clinical trial for patients with this life threatening malignancy. Project Narrative: The ultimate goal of this proposal is the development of a novel and improved immunotherapy therapy for melanoma, a tumor for which the current therapies do not offer satisfactory results. This therapy is based on activation of immune cells that will be manipulated in the laboratory and put back to patient to fight 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.