A membrane-based immunotherapy for triple negative breast cancer

描述（由申请人提供）：三阴性乳腺癌（TNBC），包括缺乏雌激素、孕激素和HER-2受体蛋白的肿瘤，占美国所有乳腺癌诊断的15-20%，是肿瘤切除后开发有效治疗最具挑战性的癌症之一。即使采用传统的放疗和化疗方案，患者的预后也很差，与其他乳腺癌相比，患者会经历早期、频繁的复发。迫切需要新的治疗方法。我们建议开发和测试一种治疗转移性TNBC的免疫疗法，使用一种个性化、易于完成、不需要建立细胞系或基因转移的方法。这种专有的癌症免疫治疗技术的定义原理是将糖脂锚定形式的免疫刺激分子（GPI-ISMs），如B7-1和IL-12，结合到手术切除的患者组织的肿瘤膜泡（TMV）上。我们期望这些附着在膜上的免疫刺激分子能够同时传递肿瘤抗原和激活免疫细胞，从而促进有效的抗肿瘤免疫反应。拟议疫苗的新颖之处不在于使用免疫刺激分子，而在于它们的使用方式。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开发癌症疫苗的研究有很大不同。主要的优点是免疫治疗准备可以在几天内完成。此外，肿瘤膜制剂可以作为冷冻等分液和生物库储存，用于加强注射。这些因素将显著降低免疫疗法生产和治疗的成本。在这个I期应用中，我们将使用这种蛋白转移技术进行基于膜的乳腺癌免疫治疗，并在小鼠模型中测试其抑制三阴性乳腺癌转移的有效性。具体来说，我们将：1)制造GPI-ISMs，优化TMV加工和蛋白转移，并使用小鼠转移性TNBC模型评估疗效；2)(a)确定膜免疫疗法是否能预防/减少TNBC的转移。(B)探讨联合使用抗免疫抑制剂是否能增强基于膜的TNBC免疫治疗的疗效。拟议的SBIR I期可行性研究的完成将证明膜基免疫疗法在抑制三阴性乳腺癌转移生长方面的有效性。这将为大规模生产纯化的人gpi分子的毒性和GMP/GLP条件标准化等II期研究铺平道路，这将有助于我们将疫苗产品推进到人体临床试验。

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.