Human T-Cell Responses to Tumor Antigens

人类 T 细胞对肿瘤抗原的反应

• 批准号: 7592699
• 负责人: JEFFREY SCHLOM
• 金额: $ 202.75万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7592699
• 关键词: Achievement; Agonist; Antibodies; Ascaridil; Bladder; Boxing; Brachyury protein; CC49 antibody; Cancer Biology; Cancer Patient; Cancer Vaccines; Carcinoma; Cell Line; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Cohort Studies; Colon; Colorectal Cancer; Combination Chemotherapy; Combined Modality Therapy; Combined Vaccines; Computer Simulation; Computers; Cytolysis; Cytotoxic T-Lymphocytes; Data; Databases; Development; Drug Kinetics; Embryonic Development; End Point; Epithelial; Epitopes; Expressed Sequence Tags; Failure; Family; Genes; Genus Cola; Hair; Head and Neck Squamous Cell Carcinoma; Hematopoietic Neoplasms; Human; Immune; Immunobiology; Immunologic Adjuvants; Immunotherapy; International; Kidney; Knowledge; Lung; Maintenance; Malignant Neoplasms; Martens; Mediating; Medicine; Mesenchymal; Mesoderm; Methodology; Mining; Modality; Mus; Neoplasm Metastasis; Normal tissue morphology; Ontario; Ovary; Patients; Phase I Clinical Trials; Phase II Clinical Trials; Phenotype; Pilot Projects; Population; Process; Prostate; Prostate Cancer Vaccine; Prostate carcinoma; Published Comment; Radiation; Randomized; Recombinant Vaccines; Reverse Transcriptase Polymerase Chain Reaction; Role; Safety; Schedule; Small Intestinal Neoplasm; Stomach; Structure of base of prostate; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Testis; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Translating; Treatment Protocols; Tumor Antigens; United States Food and Drug Administration; Update; Urogenital Cancer; Uterus; Vaccine Clinical Trial; Vaccine Therapy; Vaccines; Vaccinia virus; Viral Vector; Writing; androgen independent prostate cancer; base; cancer cell; cancer immunotherapy; cancer therapy; chemotherapeutic agent; cohort; dalton; docetaxel; humanized monoclonal antibodies; killings; mRNA Differential Displays; member; metastatic process; neoplastic cell; novel; pre-clinical; research clinical testing; response; selective expression; symposium; tool; transcription factor; tumor; tumor progression

Major scientific achievements include: the identification of mechanisms and methodologies that can be translated to enhance human T-cell responses to human tumor-associated antigens (TAAs), the identification and characterization of new targets that can be employed in vaccine-mediated immunotherapy, and the identification of agonist epitopes of human TAAs to enhance human T-cell responses. A major review has been written defining new paradigms to be employed in both vaccine clinical trial design and clinical trial endpoint. The field of cancer vaccines is currently in an active state of preclinical and clinical investigations. While no therapeutic cancer vaccine has to date been approved by the FDA, several new paradigms are emerging from recent clinical findings in both the use of combination therapy approaches and, perhaps more importantly, in clinical trial design and endpoint analyses. This review article/commentary reviewed recent clinical trials involving several different cancer vaccines from which data are emerging contrasting classical tumor response (RECIST) criteria with patient response in the manifestation of increased patient survival post-vaccine therapy. Also described are several strategies in which cancer vaccines can be exploited in combination with other agents and therapeutic modalities that are quite unique when compared with conventional combination therapies. This is most likely due to the phenomena that (a) cancer vaccines initiate a dynamic immune process that can be exploited in subsequent therapies, and (b) both radiation and certain chemotherapeutic agents have been shown to alter the phenotype of tumor cells as to render them more susceptible to T-cellmediated killing. Consequently, evidence is emerging from several studies in which patient cohorts who first receive a cancer vaccine (as contrasted with control cohorts) benefit clinically from subsequent therapies. The paradigm shifts put forth in this article for the use and clinical evaluation of cancer vaccines will hopefully result in vaccines being evaluated in more appropriate patient populations and with more appropriate clinical endpoints. Moreover, this article describes how cancer vaccines are quite distinct from conventional therapies and how vaccines can be used uniquely in combination therapeutic regimens. Other advances for this project include the identification of tumor antigens that are essential in advancing immune-based therapeutic interventions in cancer. Particularly attractive targets are molecules selectively expressed by the malignant cells and that are also essential for tumor progression. We have used a computer-based differential display (CDD) analysis tool for mining of expressed sequence tag (EST) clusters in the human Unigene database and identified Brachyury as a novel tumor antigen. Brachyury, a member of the T-box transcription factor family, is a key player in mesoderm specification during embryonic development. Transcription factors that control mesoderm, moreover, have been implicated in the epithelial-mesenchymal transition (EMT), which has been postulated to be a key step during tumor progression to metastasis. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis validated the in silico predictions and demonstrated Brachyury expression in tumors of the small intestine, stomach, kidney, bladder, uterus, ovary, and testis, as well as in cell lines derived from lung, colon, and prostate carcinomas, but not in the vast majority of the normal tissues tested. An HLAA0201 epitope of human Brachyury was identified that was able to expand T-lymphocytes from blood of cancer patients and normal donors with the ability to lyse Brachyury expressing tumor cells. To our knowledge, this is the first demonstration that (a) a T-box transcription factor and (b) a molecule implicated in mesodermal development, i.e., epithelial-mesenchymal transition (EMT), can be a potential target for human T-cell mediated cancer immunotherapy. This is important because this molecule appears to be necessary for the initiation and/or maintenance of the metastatic process. Other accomplishments of this project include: Cancer vaccines: moving beyond current paradigms. Schlom J, Arlen PM, and Gulley JL. Clin. Cancer Res. 13:3776-3782, 2007 The role of vaccine therapy in cancer: biology and practice. Schlom J, Gulley JL, and Arlen PM. Curr. Oncol. (in press) Identification of cytotoxic T-lymphocyte epitope(s) and its agonist epitope(s) of a novel target for vaccine therapy (PAGE4). Yokokawa J, Bera T, Palena C, Cereda V, Remondo C, Gulley JL, Arlen PM, Pastan I, Schlom J, and Tsang KY. Int. J. Cancer 121:595-605, 2007. The human T-box mesodermal transcription factor Brachyury is a candidate target for T-cell mediated cancer immunotherapy. Palena C, Polev DE, Tsang KY, Fernando RI, Litzinger M, Krukovskaya LL, Baranova AV, Kozlov AP, and Schlom J.Clin Cancer Res. 13:2471-2478, 2007. Population pharmacokinetics of humanized monoclonal antibody HuCC49∆CH2 and murine antibody CC49 in colorectal cancer patients. Fang L, Holford NH, Hinkle G, Cao X, Xiao JJ, Bloomston M, Gibbs S, Saif OH, Dalton JT, Chan KK, Schlom J, Martin EW Jr., and Sun D. J. Clin. Pharmacol. 47:227-237, 2007. Local delivery of vaccinia virus expressing multiple costimulatory molecules for the treatment of established tumors. Kaufman HL, Cohen S, Cheung K, DeRaffele, Mitcham J, Moroziewicz D, Schlom J, and Hesdorffer C.Human Gene Ther. 17:239-244, 2006. Preclinical and clinical studies of recombinant vaccines for carcinoma therapy. Arlen PM, Gulley JL, Madan RA, Hodge JW, and Schlom J. Crit. Rev. Immunol. (11th International Symposium of Immunobiology Supplement) (in press) Combining vaccines with conventional therapies for cancer. Arlen PM, Madan RA, Hodge JW, Schlom J, and Gulley JL. Update on Cancer Therapeutics (in press) Phase I trial of an enhanced prostate-specific antigenbased vaccine with antiCTLA-4 antibody in patients with metastatic androgen-independent prostate cancer. Theoret MR, Arlen PM, Pazdur M, Dahut WL, Schlom J, and Gulley JL. Clin. Genitourinary Cancer 5:347-350, 2007 Clinical safety of a viral vector-based prostate cancer vaccine strategy. rlen PM, Skarupa L, Pazdur M, Seetharam M, Tsang KY, Grosenbach DW, Feldman J, Poole DJ, Litzinger M, Steinberg SM, Jones E, Chen C, Marte J, Parnes H, Wright J, Dahut W, Schlom J, and Gulley JL. J. Urol. (in press; scheduled for Oct. 2007) A pilot study of CTLA-4 blockade after cancer vaccine failure in patients with advanced malignancy. OMahony D, Morris JC, Quinn C, Gao W, Wilson WH, Gause B, Pittaluga S, Neelapu S, Brown M, Fleisher TA, Gulley JL, Schlom J, Nussenblatt R, Albert P, Davis TA, Lowy I, Petrus M, Waldmann TA, and Janik JE. Clin. Cancer Res. 13:958-964, 2007. Combination chemotherapy and radiation of human squamous cell carcinoma of the head and neck augments CTL-mediated lysis. Gelbard A, Garnett CT, Abrams SI, Patel V, Gutkind JS, Palena C, Tsang KY, Schlom J, and Hodge JW. Clin. Cancer Res. 12:1897-1905, 2006. A randomized phase II study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgen independent prostate cancer. Arlen PM, Gulley JL, Parker C, Skarupa L, Pazdur M, Panicali D, Beetham P, Tsang KY, Grosenbach DW, Feldman J, Steinberg SM, Jones E, Chen C, Marte J, Schlom J, and Dahut W. Clin Cancer Res 12:1260-1269, 2006. Vaccines and immunostimulants by Hodge JW, Schlom J, Abrams SI. In: Eds: Kufe DW, Bast Jr. RC, Hair WN, et al. Holland-Frei Cancer Medicine e. 7 Hamilton, Ontario: BC Decker, 2006, Chapter 51, pp. 786-801

主要科学成就包括：确定可转化为增强人类 T 细胞对人类肿瘤相关抗原 (TAA) 反应的机制和方法，确定和表征可用于疫苗介导的免疫治疗的新靶标，以及鉴定人类 TAA 的激动剂表位以增强人类 T 细胞反应。已经撰写了一篇重要评论，定义了疫苗临床试验设计和临床试验终点所采用的新范式。癌症疫苗领域目前正处于临床前和临床研究的活跃状态。虽然迄今为止还没有治疗性癌症疫苗获得 FDA 批准，但最近在联合治疗方法的使用以及（也许更重要的是）临床试验设计和终点分析方面的临床发现正在出现一些新的范例。这篇综述文章/评论回顾了最近涉及几种不同癌症疫苗的临床试验，从中得出的数据将经典肿瘤反应 (RECIST) 标准与疫苗治疗后患者生存率增加的患者反应进行了对比。还描述了几种策略，其中癌症疫苗可以与其他药剂和治疗方式联合使用，与传统的联合疗法相比，这些策略和治疗方式非常独特。这很可能是由于以下现象：（a）癌症疫苗启动可在后续治疗中利用的动态免疫过程，以及（b）放射线和某些化疗药物已被证明可以改变肿瘤细胞的表型，从而使它们更容易受到 T 细胞介导的杀伤。因此，几项研究中出现的证据表明，首次接受癌症疫苗的患者群体（与对照群体相比）从后续治疗中获得临床获益。本文提出的癌症疫苗的使用和临床评估范式转变有望导致疫苗在更合适的患者群体中进行评估，并具有更合适的临床终点。此外，本文还介绍了癌症疫苗与传统疗法的显着不同，以及疫苗如何在联合治疗方案中独特使用。该项目的其他进展包括识别肿瘤抗原，这对于推进基于免疫的癌症治疗干预至关重要。特别有吸引力的靶标是恶性细胞选择性表达的分子，它们对于肿瘤进展也至关重要。我们使用基于计算机的差异显示（CDD）分析工具挖掘人类 Unigene 数据库中的表达序列标签（EST）簇，并将 Brachyury 鉴定为一种新型肿瘤抗原。 Brachyury 是 T-box 转录因子家族的成员，是胚胎发育过程中中胚层规范的关键角色。此外，控制中胚层的转录因子与上皮间质转化（EMT）有关，这被认为是肿瘤进展到转移过程中的关键步骤。逆转录酶聚合酶链反应 (RT-PCR) 分析验证了计算机预测，并证明 Brachyury 在小肠、胃、肾、膀胱、子宫、卵巢和睾丸的肿瘤以及源自肺、结肠癌和前列腺癌，但不在绝大多数测试的正常组织中。鉴定出人类 Brachyury 的 HLAA0201 表位能够扩增癌症患者和正常供体血液中的 T 淋巴细胞，并能够裂解表达 Brachyury 的肿瘤细胞。据我们所知，这是首次证明 (a) T-box 转录因子和 (b) 与中胚层发育（即上皮间质转化 (EMT)）有关的分子可以成为人类 T 细胞的潜在靶标介导的癌症免疫治疗。这很重要，因为该分子似乎对于转移过程的启动和/或维持是必需的。该项目的其他成就包括： 癌症疫苗：超越当前范式。施洛姆 J、阿伦 PM 和格利 JL。临床。癌症研究中心。 13:3776-3782, 2007 疫苗治疗在癌症中的作用：生物学和实践。 Schlom J、Gulley JL 和 Arlen PM。电流。安科尔。 （正在出版）疫苗治疗新靶标的细胞毒性 T 淋巴细胞表位及其激动剂表位的鉴定 (PAGE4)。 Yokokawa J、Bera T、Palena C、Cereda V、Remondo C、Gulley JL、Arlen PM、Pastan I、Schlom J 和 Tsang KY。国际。 J. Cancer 121:595-605, 2007。人类 T-box 中胚层转录因子 Brachyury 是 T 细胞介导的癌症免疫治疗的候选靶点。 Palena C、Polev DE、Tsang KY、Fernando RI、Litzinger M、Krukovskaya LL、Baranova AV、Kozlov AP 和 Schlom J.Clin 癌症研究中心。 13:2471-2478, 2007。人源化单克隆抗体 HuCC49ΔCH2 和鼠抗体 CC49 在结直肠癌患者中的群体药代动力学。 Fang L、Holford NH、Hinkle G、Cao X、Xiao JJ、Bloomston M、Gibbs S、Saif OH、Dalton JT、Chan KK、Schlom J、Martin EW Jr. 和 Sun D. J. Clin。药理学。 47:227-237, 2007。局部递送表达多种共刺激分子的痘苗病毒以治疗已形成的肿瘤。 Kaufman HL、Cohen S、Cheung K、DeRaffele、Mitcham J、Moroziewicz D、Schlom J 和 Hesdorffer C.人类基因疗法。 17:239-244, 2006。用于癌症治疗的重组疫苗的临床前和临床研究。 Arlen PM、Gulley JL、Madan RA、Hodge JW 和 Schlom J. Crit。免疫学牧师。 （第 11 届国际免疫生物学研讨会增刊）（正在出版）将疫苗与常规癌症疗法相结合。 Arlen PM、Madan RA、Hodge JW、Schlom J 和 Gulley JL。癌症治疗更新（正在出版）针对转移性雄激素非依赖性前列腺癌患者，使用抗 CTLA-4 抗体增强前列腺特异性抗原疫苗的 I 期试验。 Theoret MR、Arlen PM、Pazdur M、Dahut WL、Schlom J 和 Gulley JL。临床。泌尿生殖癌 5:347-350, 2007 基于病毒载体的前列腺癌疫苗策略的临床安全性。 rlen PM、Skarupa L、Pazdur M、Seetharam M、Tsang KY、Grosenbach DW、Feldman J、Poole DJ、Litzinger M、Steinberg SM、Jones E、Chen C、Marte J、Parnes H、Wright J、Dahut W、Schlom J和格利 JL。 J.乌罗尔。 （正在出版；计划于 2007 年 10 月）在晚期恶性肿瘤患者中进行癌症疫苗失败后 CTLA-4 阻断的试点研究。 OMahony D、莫里斯 JC、奎因 C、高 W、威尔逊 WH、高斯 B、皮塔卢加 S、尼拉普 S、布朗 M、弗莱舍 TA、格利 JL、施洛姆 J、努森布拉特 R、阿尔伯特 P、戴维斯 TA、洛伊 I、佩特鲁斯 M 、Waldmann TA 和 Janik JE。临床。癌症研究中心。 13:958-964, 2007。人类头颈部鳞状细胞癌的联合化疗和放疗增强了 CTL 介导的裂解。 Gelbard A、Garnett CT、Abrams SI、Patel V、Gutkind JS、Palena C、Tsang KY、Schlom J 和 Hodge JW。临床。癌症研究中心。 12:1897-1905, 2006。一项针对转移性雄激素非依赖性前列腺癌同时多西紫杉醇加疫苗与单独疫苗的随机 II 期研究。 Arlen PM、Gulley JL、Parker C、Skarupa L、Pazdur M、Paicali D、Beetham P、Tsang KY、Grosenbach DW、Feldman J、Steinberg SM、Jones E、Chen C、Marte J、Schlom J 和 Dahut W. Clin Cancer Res 12:1260-1269, 2006。疫苗和免疫刺激剂，作者：Hodge JW、施洛姆 J、艾布拉姆斯 SI。见：编辑：Kufe DW、Bast Jr. RC、Hair WN 等。 Holland-Frei 癌症医学 e． 7 安大略省汉密尔顿：BC Decker，2006 年，第 51 章，第 786-801 页