Immunotherapeutic Approaches to Cancer Treatment

描述(申请人提供)：免疫疗法作为一种治疗癌症的方法已经得到了深入的研究，但很少有研究产生有意义的临床反应。近年来，随着对肿瘤中许多可被T淋巴细胞识别的抗原的识别和描述，肿瘤免疫学的许多基本原理得到了阐明。疫苗接种策略也已经被开发出来，以诱导针对这些肿瘤抗原的免疫反应，并被证明在患者中诱导T细胞反应。然而，显示接种疫苗后癌症消退的客观反应的研究数量有限。对这种最低应答率的一种解释是，用于这些试验的疫苗在人类身上的免疫原性太低，无法诱导足够大的反应来导致癌症消退。该项目的长期目标是确定基于重组巨细胞病毒(RCMV)的疫苗在癌症系统免疫治疗中的效用。人巨细胞病毒(Human CMV，HCMV)是一种高度免疫原性的病毒，可在人体内持续终生感染。大约一半的美国人曾接触过HCMV感染，这一点从血清中发现的针对特定病毒表位的抗体(血清阳性)中得到了证明。作为疫苗，该病毒具有独特的特征，包括：1)在免疫正常的宿主中没有与HCMV感染相关的疾病，2)能够再次感染HCMV血清阳性者，3)对异种DNA具有很大的携带能力，4)在宿主内持续很长时间，5)诱导大量的免疫反应(在无症状感染者中，10-20%的CD4+和CD8+记忆T细胞都针对HCMV抗原)。这种基于rCMV的疫苗正在开发中，可以表达明确的异源靶标抗原，有望成为流感和艾滋病毒等传染病的疫苗。这项建议的目的是扩大这些观察结果，以确定表达癌症相关靶抗原的CMV载体作为癌症免疫治疗的能力。作为癌症治疗的免疫治疗已被深入研究，但很少有研究产生有意义的临床反应。这项建议的目的是确定巨细胞病毒为基础的载体表达癌症相关的靶抗原作为癌症免疫治疗的能力。

DESCRIPTION (provided by applicant): Immunotherapy as a treatment for cancer has been intensely investigated, but few studies have resulted in meaningful clinical responses. Many fundamental principals of tumor immunology have been clarified in recent years with the recognition and description of many antigens in tumors that can be recognized by T lymphocytes. Vaccination strategies to induce an immune response against these tumor antigens have also been developed and shown to induce a T cell response in patients. However, studies showing an objective response of cancer regression following vaccination are limited in number. One explanation for this minimal response rate is that the immunogenicity of the vaccines used for these trials in humans is too low to induce a response of sufficient magnitude to result in cancer regression. The long-term goal of this project is to determine the utility of recombinant cytomegalovirus (rCMV)-based vaccines for systemic immunotherapy for cancer. Human CMV (hCMV) is a highly immunogenic virus that results in persistent, life-long infection in the human host. About half of the U.S. population has been exposed to hCMV infection as demonstrated by the finding of antibodies to defined viral epitopes in the serum (seropositive). The virus has unique characteristics as a vaccine including: 1) lack of disease associated with hCMV infection in the immune-normal host, 2) ability to re-infect hCMV-seropositive individuals, 3) large carrying capacity for heterologous DNA, 4) life-long persistence within the host corresponding to 5) induction of a large immune response (10-20% of both the CD4+ and CD8+ memory T cells directed against hCMV antigens in asymptomatically infected individuals). Such rCMV-based vaccines expressing defined heterologous target antigens are being developed and have promise as vaccines for infectious disease such as influenza and HIV. The purpose of this proposal is to extend these observations to determine the capacity of CMV-based vectors expressing cancer-associated target antigens as an immunotherapy for cancer.Immunotherapy as a treatment for cancer has been intensely investigated, but few studies have resulted in meaningful clinical responses. The purpose of this proposal is to determine the capacity of CMV-based vectors expressing cancer-associated target antigens as an immunotherapy for cancer.