Lentiviral Vectors for TCR Immunotherapy Targeted to melanoma

项目摘要/摘要：本提案的总体目标是评估使用慢病毒工程T细胞表达高亲和力T细胞受体（TCR），能够识别酪氨酸酶：368-376表位，黑色素瘤/黑色素细胞分化肿瘤相关抗原，是否提高了黑色素瘤免疫治疗的疗效。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。在这个提议中，我们将测试一个基本假设，即使用慢病毒载体技术可以创建具有黑色素瘤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治疗黑色素瘤的方法，目前的治疗方法不能提供令人满意的结果。慢病毒载体（LVs）已在艾滋病毒/艾滋病患者的i期临床试验中得到成功评估，为更广泛地应用这项技术治疗其他疾病，特别是癌症提供了可能性。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，在本提案的目标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链和B链的自我失活（SIN） lv。在Aim 2中，我们将与Nishimura博士的团队一起，在体内测试LV-TCR转导T细胞在预防黑色素瘤肿瘤生长和治疗已建立肿瘤方面的安全性和有效性。我们将进行两种一般类型的实验，以测试我们的慢病毒载体在工程人类T细胞中表达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，可以首次全面评估重定向T细胞方法在黑色素瘤患者中产生的抗肿瘤作用，并将其应用于这种威胁生命的恶性肿瘤患者的未来临床试验。项目描述：本提案的最终目标是开发一种新的和改进的黑色素瘤免疫疗法，目前的治疗方法不能提供令人满意的结果。这种疗法基于免疫细胞的激活，这些免疫细胞将在实验室中被操纵，并被放回患者体内，以对抗黑色素瘤肿瘤细胞。由于它有很大的潜力为那些其他疗法失败的患者提供解决方案，这种疗法将对美国和全世界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.