Clinical Evaluation of a Personalized Vaccine Immunotherapy in Combination with Checkpoint Inhibitors for Triple Negative Breast Cancer

补充补助金摘要： 乳腺癌是女性癌症相关死亡率最高的疾病。在其亚型中，转移性三重 阴性乳腺癌(TNBC)预后最差，很大程度上是由于对现有治疗方法的抵抗。 雌激素受体、孕激素受体和HER-2蛋白表达缺失。最近的研究采用了 免疫检查点抑制(ICI)疗法提示TNBC可能是ICI治疗的良好靶点，因为 存在高水平的浸润性淋巴细胞。然而，大多数TNBC癌症患者并不是这样 由于缺乏预先存在的免疫力，对ICI治疗有反应。为了开发更有效的治疗方法，它 为TNBC患者设计一种克服肿瘤内和患者之间的治疗方法是很重要的 异质性。Metaclipse Treateutics一直致力于开发一种个性化疫苗，以解决 异质性。利用一种新的蛋白质转移方法，我们产生了来源于 并用糖脂锚定形式的免疫刺激分子(GPI-1)修饰它们。 表达B7-1和白介素12(IL-12)。我们的数据表明，TMV疫苗是从 同基因肿瘤在多种癌症小鼠模型中都有效。然而，目前还不清楚是否 作为乳腺癌治疗标准的新辅助化疗影响TMV的产量和质量。 基础疫苗。我们假设标准护理(SOC)化疗的增加通常是 TNBC患者手术前给予TMV疫苗会影响TMV疫苗的产量和质量。致信地址 对此，提出了以下具体目标。目的1，明确新辅助化疗对患者预后的影响。 TMV疫苗的产量和质量。目的2，明确新辅助化疗对人卵巢癌治疗能力的影响。 TMV疫苗体外刺激APC和自体T细胞。本补充建议的家长拨款 将进行第一阶段临床试验，以评估TMV疫苗在TNBC患者中的耐受性。本研究 将提供对新辅助化疗如何影响TMV疫苗的理解 从TNBC肿瘤中制备。

Abstract of the supplemental grant: Breast cancer accounts for the highest cancer-related mortality in women. Among its subtypes, metastatic triple negative breast cancer (TNBC) has the worst prognosis largely due to resistance to currently available therapies and lack of estrogen receptor, progesterone receptor and HER-2 protein expression. Recent studies employing immune checkpoint inhibitor (ICI) therapies suggest that TNBC may be a good target for ICI therapy due to the presence of high level of infiltrating lymphocytes. However, the majority of the TNBC cancer patients do not respond to ICI therapy due to the lack of pre-existing immunity. In order to develop more effective treatments, it is important to design a therapeutic approach for TNBC patients which overcomes intra-tumoral and inter-patient heterogeneity. Metaclipse Therapeutics has been engaged in developing a personalized vaccine to address heterogeneity. Utilizing a novel protein transfer method, we generate tumor membrane vesicles (TMVs) derived from whole tumor tissues and modify them with glycolipid-anchored forms of immunostimulatory molecules (GPI- ISMs) expressing B7-1 and interleukin-12 (IL-12). Our data demonstrates that TMV vaccines prepared from syngeneic tumors are effective in multiple murine models of cancer. However, it is currently unknown if neoadjuvant chemotherapy which is a standard of care for breast cancer affects the yield and quality of TMV- based vaccines. We hypothesize that the addition of standard-of-care (SOC) chemotherapy which is usually administered in TNBC patients before surgery impacts the yield and quality of TMV-based vaccines. To address this, the following specific aims are proposed. Aim 1, To define the impact of neoadjuvant chemotherapy on the yield and quality of the TMV vaccine. Aim 2, To define the impact of neoadjuvant chemotherapy on the ability of TMV vaccine to stimulate APCs and autologous T cells ex vivo. The parent grant of this supplement proposal will be conducting Phase 1 clinical trial to evaluate the tolerability of TMV vaccine in TNBC patients. This study will provide an understanding about how the neoadjuvant chemotherapy impacts the TMV-based vaccines prepared from TNBC tumors.