Immunotherapeutic Approaches to Cancer Treatment

描述（由申请人提供）：免疫疗法作为一种治疗癌症的方法已经得到了广泛的研究，但很少有研究产生有意义的临床反应。近年来，随着T淋巴细胞对肿瘤中许多抗原的识别和描述，肿瘤免疫学的许多基本原理得到了澄清。诱导针对这些肿瘤抗原的免疫应答的疫苗接种策略也已被开发出来，并显示在患者中诱导T细胞应答。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。对这种最低反应率的一种解释是，这些人体试验中使用的疫苗的免疫原性太低，无法诱导足够大的反应，导致癌症消退。该项目的长期目标是确定重组巨细胞病毒（rCMV）疫苗在癌症全身免疫治疗中的效用。人类巨细胞病毒（hCMV）是一种高度免疫原性病毒，可导致人类宿主持续终生感染。大约一半的美国人暴露于hCMV感染，这是通过在血清中发现针对特定病毒表位的抗体（血清阳性）来证明的。该病毒作为疫苗具有独特的特点，包括：1)在免疫正常的宿主中缺乏与hCMV感染相关的疾病，2)能够再次感染hCMV血清阳性的个体，3)外源DNA的大携带能力，4)在宿主内终生存在，5)诱导大量免疫应答（在无症状感染的个体中，10-20%的CD4+和CD8+记忆T细胞直接针对hCMV抗原）。这种基于rcmv的疫苗正在开发中，表达明确的异源靶抗原，有望成为流感和艾滋病毒等传染病的疫苗。本提案的目的是扩展这些观察结果，以确定表达癌症相关靶抗原的基于cmv的载体作为癌症免疫治疗的能力。免疫疗法作为一种治疗癌症的方法已经得到了广泛的研究，但很少有研究产生有意义的临床反应。本提案的目的是确定表达癌症相关靶抗原的基于cmv的载体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.