A membrane-based immunotherapy for triple negative breast cancer

针对三阴性乳腺癌的基于膜的免疫疗法

基本信息

批准号：
8524714
负责人：
CHRISTOPHER D PACK
金额：
$ 14.48万
依托单位：
METACLIPSE THERAPEUTICS CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-21 至 2014-08-20
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8524714
关键词：
Accounting Adjuvant Aliquot Antigen Targeting Biological Assay Brain Breast Cancer Cell Breast Cancer Model CD80 gene CD8B1 gene Cancer Patient Cancer Vaccines Cancer cell line Cell Culture Techniques Cell Line Cells Chemotherapy-Oncologic Procedure Clinic Clinical Trials Cyclophosphamide Diagnosis Disease Progression Dose ERBB2 gene Environment Estrogens Evaluation Excision Feasibility Studies Freezing Gene Mutation Gene Transfer Gene Transfer Techniques Genetic Variation Glycolipids Growth Heterogeneity Human Immune Immune response Immunosuppression Immunosuppressive Agents Immunotherapeutic agent Immunotherapy Infiltration Injection of therapeutic agent Interleukin-12 Lung Malignant Neoplasms Mediation Medicine Membrane Modeling Mus Neoplasm Metastasis Operative Surgical Procedures Patients Phase Phenotype Preparation Primary Neoplasm Process Production Progesterone Proteins Radiation Radiosurgery Recurrence Regulatory T-Lymphocyte Relapse Research Resected Small Business Innovation Research Grant Solid Neoplasm Sorting - Cell Movement Standardization T cell response T-Lymphocyte Techniques Technology Testing Therapeutic Tissues Toxic effect Tumor Antigens Tumor Cell Line Tumor Immunity Universities Up-Regulation Vaccination Vaccines Vesicle Woman base biobank breast cancer diagnosis cancer immunotherapy chemotherapy cost cost effective cytokine dosage early experience effective therapy efficacy testing falls frontier large scale production malignant breast neoplasm neoplastic cell novel outcome forecast phase 2 study prevent public health relevance receptor response scale up triple-negative invasive breast carcinoma tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Triple negative breast cancer (TNBC), which includes tumors lacking estrogen, progesterone, and HER-2 receptor proteins, represents 15-20% of all breast cancer diagnoses in the US, and is one of the most challenging cancers for developing an effective therapy post tumor resection. Even with conventional radiation and chemotherapy regimens, patients have poor prognosis, experiencing early, frequent relapses in comparison to other breast cancers. New therapies are critically needed. We propose to develop and test an immunotherapy to treat metastatic TNBC using an approach that is personalized, easy to accomplish, and not requiring establishment of cell lines or gene transfer. The defining principle of this proprietary cancer immunotherapy technology is the incorporation of glycolipid anchored forms of immunostimulatory molecules (GPI-ISMs), such as B7-1 and IL-12, onto tumor membrane vesicles (TMV) derived from surgically removed patient tissue. We expect that these membrane attached immunostimulatory molecules will simultaneously deliver tumor antigens and activate immune cells to promote an effective anti-tumor immune response. The novelty of the proposed vaccine lies not in the use of immunostimulatory molecules but in the way they are employed. The protein transfer approach is substantially different from previous studies that used gene transfer techniques or secretory cytokines to develop cancer vaccines. The major advantage is that the immunotherapy preparation can be accomplished within just a few days. Additionally, tumor membrane preparations can be stored as frozen aliquots and biobanked for booster injections. These factors will significantly reduce the cost of immunotherapy production and treatment. In this Phase I application, we will use this protein transfer technique for membrane-based breast cancer immunotherapy and test its efficacy in inhibiting triple negative breast cancer metastasis in a murine model. Specifically, we will: 1) manufacture GPI-ISMs, optimize TMV processing and protein transfer, and evaluate efficacy using a murine metastatic TNBC model, 2) (A) Determine whether the membrane-based immunotherapy prevents/reduces metastasis of TNBC. (B) Investigate whether co-administration of anti-immunosuppressive agents augments efficacy of the membrane- based TNBC immunotherapy. Completion of the proposed SBIR Phase I feasibility studies will demonstrate the efficacy of membrane-based immunotherapy in inhibiting the metastatic growth of triple negative breast cancers. This will pave the way for Phase II studies such as toxicity and standardization of GMP/GLP conditions for large-scale production of purified human GPI-molecules, which will help us advance the vaccine product to human clinical trials.

描述（由申请人提供）：包括缺乏雌激素，孕酮和HER-2受体蛋白的肿瘤三重阴性乳腺癌（TNBC），占美国所有乳腺癌诊断的15-20％，并且是开发有效治疗后肿瘤后切除疗法治疗的最具挑战性的癌症之一。即使使用常规的放射线和化学疗法方案，患者的预后也很差，与其他乳腺癌相比，患者的早期复发经常复发。需要新的疗法。我们建议使用个性化，易于完成的方法开发和测试免疫疗法，以治疗转移性TNBC，并且不需要建立细胞系或基因转移。该专有癌症免疫疗法技术的定义原理是将糖脂锚定形式的免疫刺激分子（GPIISS）（例如B7-1和IL-12）纳入肿瘤膜囊泡（TMV）（TMV）。我们预计这些膜附着的免疫刺激性分子将同时提供肿瘤抗原并激活免疫细胞以促进有效的抗肿瘤免疫反应。所提出的疫苗的新颖性在于使用免疫刺激分子，而在于使用它们的方式。蛋白质转移方法与以前使用基因转移技术或分泌细胞因子进行癌症疫苗的研究大大不同。主要优点是可以在短短几天内完成免疫疗法的准备。此外，肿瘤膜制剂可以作为冷冻等分试样存储，并为增强注射生物群。这些因素将大大降低免疫疗法生产和治疗的成本。在此I阶段应用中，我们将使用这种蛋白质转移技术进行基于膜的乳腺癌免疫疗法，并在鼠模型中测试其在抑制三重阴性乳腺癌转移方面的功效。具体而言，我们将：1）生产GPIIS，优化TMV处理和蛋白质转移，并使用鼠转移性TNBC模型评估功效，2）（a）确定基于膜的免疫疗法是否预防/减少TNBC的转移。（b）研究抗免疫抑制剂的共同给药是否会增强基于膜的TNBC免疫疗法的功效。提出的SBIR I期可行性研究的完成将证明基于膜的免疫疗法在抑制三重阴性乳腺癌的转移性生长方面的疗效。这将为II期研究铺平道路，例如用于大规模生产纯化的人类GPI摩尔分子的GMP/GLP条件的毒性和标准化，这将有助于我们将疫苗产品推向人类临床试验。