Immunotherapeutic Approaches to Cancer Treatment

描述（由申请人提供）：免疫疗法作为癌症的治疗方法已被深入研究，但很少有研究产生有意义的临床反应。近年来，随着T淋巴细胞识别肿瘤中多种抗原的发现和描述，肿瘤免疫学的许多基本原理已得到阐明。还开发了诱导针对这些肿瘤抗原的免疫应答的疫苗接种策略，并显示其在患者中诱导T细胞应答。然而，显示接种疫苗后癌症消退的客观缓解的研究数量有限。对这种最低应答率的一种解释是，用于这些人体试验的疫苗的免疫原性太低，无法诱导足以导致癌症消退的应答。该项目的长期目标是确定基于重组巨细胞病毒（rCMV）的疫苗用于癌症全身免疫治疗的效用。人CMV（hCMV）是一种高度免疫原性的病毒，其导致人类宿主中的持续、终身感染。大约一半的美国人口已经暴露于hCMV感染，如血清中确定的病毒表位的抗体的发现所证明的（血清阳性）。该病毒作为疫苗具有独特的特征，包括：1）在免疫正常宿主中缺乏与hCMV感染相关的疾病，2）再感染hCMV血清阳性个体的能力，3）对异源DNA的大携带能力，4）在宿主体内终生持续存在，对应于5）诱导大的免疫应答（在无症状感染的个体中，10-20%的CD 4+和CD 8+记忆T细胞针对hCMV抗原）。表达确定的异源靶抗原的这种基于rCMV的疫苗正在开发中，并且有望作为传染病如流感和HIV的疫苗。本提案的目的是扩展这些观察，以确定CMV为基础的载体表达癌症相关的靶抗原作为癌症的免疫疗法的能力。免疫疗法作为癌症的治疗方法已被深入研究，但很少有研究导致有意义的临床反应。本提案的目的是确定表达癌症相关靶抗原的CMV载体作为癌症免疫疗法的能力。

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.