Pre-clinical Evaluation of a Novel Immune Modulator, Alpha-TEA-Lys in Combination with Trastuzumab Against HER2/neu Positive Breast Cancer

HER2+乳腺癌(HER2+BC)是一种侵袭性乳腺癌，夺走了超过12万人的生命 世界各地每年都有妇女参加。目前HER2+BC的治疗依赖于化疗联合 曲妥珠单抗、pertuzumab和曲妥珠单抗-emtansine(TD-M1)，它们针对癌症上的HER2受体 细胞。虽然最初对这些治疗有反应，但HER2+乳腺癌最终会进展。在这些之外 被公认为具有显著临床益处的治疗方法有限，例如 拉帕替尼(一种化疗药物)在病情进展方面有好处，但对总存活率没有好处。 尽管这些疗法导致了更高的应答率，更长的进展时间和 一些转移性疾病患者的存活率，他们受到与药物相关的毒性的困扰，这些毒性长期以来 严重影响患者生活质量的长期不良反应。考虑到这些限制，HER2+ BC构成了一个重大的临床挑战，而开发有效和安全的新药物是一个关键的未完成的任务 需要。Veana Treateutics开发了一种新的临床专利候选药物a-TEA-赖氨酸(a-TEA-赖氨酸)。 可杀死癌细胞，但不能以刺激抗肿瘤免疫的方式杀死正常细胞。在临床前阶段 研究表明，a-TEA-Lys能安全有效地使已建立的糖尿病模型消退。 表达HER2/neu的肿瘤。Veana进行了人类首个a-Tea-Lys剂量递增试验 患有多种晚期癌症的患者。在测试的剂量下，α-茶氨酸是安全的，耐受性良好， 17例患者中有12例(70%)肿瘤停止生长(病情稳定)。A-Tea-Lys的安全性概况， 再加上其促凋亡和免疫刺激的特性，使其成为理想的组合候选物质 HER2特异性抗体可消除肿瘤。此应用程序的目标是进行概念验证预 α-TEA与抗-HER2/neu联合治疗最佳给药方案的临床研究 这将产生最佳的治疗结果，同时限制毒性。我们将追求三个具体目标来实现 这个目标：目标1：确定a-Tea-Lys/抗-HER2/neu联合治疗的时间表 HER2/neu+乳腺癌临床前模型的持久肿瘤消退。目标2：确定 α-TEA-Lys/抗-HER2/neu联合治疗有效的替代免疫生物标志物。目标3： α-TEA/抗-HER2/neu联合用药的抗肿瘤活性及毒副作用比较 紫杉醇/抗HER2/neu和拉帕替尼/抗HER2/neu治疗。我们将评估肿瘤的生长和存活率， 并进行血液学分析、全面尸检和对治疗后的组织器官进行检查 动物。完成研究和实现里程碑将为第二阶段的赠款奠定基础 A-TEA联合曲妥珠单抗安全性和耐受性评价 HER2+BC患者。在随后的II/III期试验中展示疗效可能导致FDA批准 为a-茶与曲妥珠单抗联合治疗HER2+BC的商业化铺平道路。

HER2+ breast cancer (HER2+ BC) is an aggressive type of breast cancer that claims the lives of over 120,000 women annually worldwide. Current treatments for HER2+ BC rely on chemotherapy in combination with trastuzumab, pertuzumab, and trastuzumab-emtansine (TD-M1), which target the HER2 receptor on cancer cells. While initially responsive to these treatments, HER2+ breast cancer eventually progress.. Beyond these therapies there are limited options recognized to have a significant clinical benefit with therapies such as Lapatinib (a chemotherapy drug) demonstrating a benefit in time to progression, but not in overall survival. Although these therapies have resulted in higher response rates, longer time to progression and increased survival in some patients with metastatic disease, they are plagued by drug-related toxicities that have long- term adverse effects that severely impact the quality of life of patients. Considering these limitations, HER2+ BC poses a major clinical challenge, and developing new agents that are effective and safe is a critical unmet need. Veana Therapeutics has developed a novel proprietary clinical drug candidate, a-TEA-Lysine (a-TEA- Lys) that kills cancer but not normal cells in a fashion that stimulates anti-tumor immunity. In pre-clinical studies, we demonstrated that a-TEA-Lys is safe and efficacious in causing regression of established HER2/neu-expressing tumors. Veana has conducted a first-in-human dose escalation trial of a-TEA-Lys in patients with multiple types of advanced cancer. At the doses tested, a-TEA-Lys was safe, well tolerated and stopped tumor from growing (stable disease) in 12 of 17 patients (70%). The safety profile of a-TEA-Lys, coupled with its pro-apoptotic and immune-stimulating properties, make it an ideal candidate to combine with HER2-specific antibody to eliminate tumors. The goal of this application is to conduct proof-of-concept pre- clinical studies to determine the optimum dosing schedule of a-TEA and anti-HER2/neu combination therapy that will yield the best therapeutic outcome while limiting toxicity. We will pursue three specific aims to achieve this goal: Aim 1: Determine the schedule of a-TEA-Lys/anti-HER2/neu combination therapy that will elicit lasting tumor regression in a well-described pre-clinical model of HER2/neu+ breast cancer. Aim 2: Identify surrogate immunologic biomarkers of effective a-TEA-Lys/anti-HER2/neu combination therapy. Aim 3: Compare the antitumor activity and toxicity profile of a-TEA/anti-HER2/neu treatment with that of paclitaxel/anti-HER2/neu and lapatinib/anti-HER2/neu treatments. We will assess tumor growth and survival, and perform hematological analysis, complete necropsy and examination of tissues and organs of treated animals. Completion of the studies and realization of the milestones will lay the groundwork for a Phase II grant application to evaluate safety and tolerability of a-TEA plus trastuzumab in a first-in-human combination trial in patients with HER2+ BC. Demonstration of efficacy in subsequent Phase II/III trials could lead to FDA-approval paving the way for commercialization of a-TEA as a companion drug with trastuzumab for treating HER2+ BC.