Phase I Trial with Two HER-2 B Cell Epitope Vaccine in Patients with Solid Tumors

描述（由申请人提供）：人体免疫系统是对抗癌症的潜在强大防线。癌症患者中存在许多生物学障碍，这些障碍可以阻碍肿瘤特异性免疫应答。虽然有令人信服的证据表明，免疫系统能够产生高度有效的抗肿瘤反应，但绝大多数免疫干预措施仅显示出适度的临床影响。由于疫苗接种诱导的免疫记忆的产生，训练免疫系统有效识别和杀死肿瘤细胞的机会可能是非常重要的。本申请中的假设是设计独特的B细胞表位肽，其可以重现肿瘤抗原的精致天然结构，并且当与“混杂的”T细胞活化物质组合时，导致产生高效的天然样抗肽抗体。我们已经在临床前研究中证明，这样的内源性抗体可以延迟、预防和/或根除肿瘤生长和转移，具有增加的功效和很少或没有毒性。因此，该项目的总体目标是通过尝试控制或治愈转移性癌症来继续在人类中测试这一假设。人表皮生长因子受体（HER）信号传导抑制在靶向癌症治疗中起主要作用。HER-2过度表达和扩增见于乳腺癌、胃癌、食管癌、子宫内膜癌、子宫癌、卵巢癌和肺癌的亚群。HER-2在HER受体家族（EGFR（HER-1）、HER-2、HER-3和HER-4）的网络中起主要协调作用。为了实现我们的目标，提出了两个目标：具体目标1：进行早期临床试验，评估免疫的安全性和临床毒性，以及建立组合疫苗的最佳生物学剂量（OBD）。具体目标二：确定联合疫苗和nor-MDP作为佐剂免疫的患者是否引起体液和细胞免疫应答，并研究体外和体内抗肿瘤活性的潜在机制。相关研究，包括最新免疫学监测、体外作用机制。在这个项目中，基础科学和临床科学将并行进行，相互通报;基础科学家和医生科学家将作为一个团队共同努力，开发基于发现的科学，改变病人的护理。公共卫生相关性：拟议的临床试验和研究计划的目标是定义工程人类免疫系统识别和摧毁致命形式的癌症所需的基本知识。HER-2肽疫苗的临床前动物和人类临床研究都指出了控制癌症的可能性。该项目将继续确定是否可以设计更好的肽疫苗，以产生高效的抗癌抗体。该项目的科学进步将对癌症产生重大的公共卫生影响。使用安全无毒的天然合成肽进行主动免疫治疗相对于使用曲妥珠单抗（赫赛汀）等mAb进行被动免疫治疗的优势是这项工作的一个基本方面。

DESCRIPTION (provided by applicant): The human immune system is a potentially powerful line of defense against cancer. Many biological obstacles exist in cancer patients that can thwart tumor specific immune responses. While there is compelling evidence that the immune system is capable of generating highly effective antitumor responses, the vast majority of immunotherapeutic interventions show only modest clinical impact. The opportunity to train the immune system to efficiently recognize and kill tumor cells could be highly significant because of the generation of immunologic memory induced by vaccination. The hypothesis in this application is that the design of unique B cell epitope peptides which can recapitulate the exquisite native structure of the tumor antigen and when combined with a "promiscuous" T cell activating species results in the production of highly efficacious native-like antipeptide antibodies. We have demonstrated in preclinical studies that such endogenous antibodies can delay, prevent and/or eradicate tumor growth and metastasis with increased efficacy and little or no toxicity. Thus, the overall goal of this project is to continue to test this hypothesis in humans by attempting to control or cure metastatic cancers. Human epidermal growth factor receptor (HER) signaling inhibition plays a major role in targeted cancer therapies. HER-2 over expression and amplification is seen in subsets of breast, gastric, esophageal, endometrial, uterine, ovarian, and lung cancers. HER-2 plays a major coordinating role in this network of family of HER receptors (EGFR (HER-1), HER-2, HER-3, and HER-4). To achieve our objectives two aims are proposed: Specific Aim 1: To perform early phase clinical trial assessing safety and clinical toxicity of immunization, as well as to establish an optimum biologically dose (OBD) of combination vaccines. Specific Aim 2: To determine whether both humoral and cellular immune responses are elicited in patients immunized with combination vaccines and nor-MDP as adjuvant and to study the underlying mechanisms of anti-tumor activity in vitro and in vivo. Correlative studies that include state of the art immunological monitoring, in vitro mechanism of action. In this project basic and clinical science will be conducted in parallel, each informing the other; basic scientists and physician-scientists will work together as a team to develop discovery-based science that will change the care of patients. PUBLIC HEALTH RELEVANCE: The proposed clinical trial and research program has as its goal to define the basic knowledge required for engineering the human immune system to recognize and destroy deadly forms of cancer. Both preclinical animal and human clinical studies with a HER-2 peptide vaccine point to the possibility of controlling cancer. This project will be to continue to determine whether better peptide vaccines can be engineered to produce cancer-killing antibodies with high efficacy. Scientific advances from this project will have a significant public health impact for cancer. The advantage of active immunotherapy with safe and non toxic natural synthetic peptides over passive immunotherapy with mAbs such as trastuzumab (Herceptin) is a fundamental aspect of this work.