IND enabling studies for a personalized immunotherapy for triple negative breast cancer

摘要 全球乳腺癌发病率为168万。三阴性乳腺癌(TNBC)占 约占总乳腺癌病例的20%(全球336,000例)。每年，超过40,000例新的TNBC病例被诊断为- 仅在美国就有业务。对于TNBC患者的治疗选择是有限的。三阴性乳腺癌 (TNBC)包括缺乏雌激素受体、孕激素受体和HER-2蛋白的乳腺癌。缺欠 已知的靶点和患者对患者的靶抗原变异使TNBC成为最具挑战性的 为癌症开发一种有效的治疗方法。迫切需要新的疗法，因为TNBC也对 单独的检查站封锁抑制。我们建议开发一种联合应用的免疫疗法。 通过检查点封锁，使用个性化的方法治疗转移性TNBC，从而将 患者特异性新抗原和其他糖基化模式上调或改变的肿瘤抗原， 如MUC-1。Metaclipse的免疫疗法(自体治疗性疫苗)由肿瘤膜组成 由患者特定的肿瘤组织制成的小泡(TMV)，携带膜相关的肿瘤抗原 以及来源于胞浆蛋白的抗原表位，作为MHC相关多肽。这些TMV就是 一种新的蛋白质直接连接到糖脂锚定的免疫刺激分子(GPI-ISM) 转让技术。提议的疫苗的新颖性不在于对ISM的使用，而在于它们的方式 受雇的。TMV和GPI-ISM之间的这种直接物理联系允许同时传递患者的 疫苗接种部位独特的肿瘤抗原标记和ISM可诱导强大的抗肿瘤免疫应答 海绵。由于TMV疫苗是由完整的肿瘤组织制备的，不仅包括患者特异性的 变异还包括所有肿瘤的异质性。我们方法的一个关键优势是免疫- 治疗产品可以在一周内准备好，这在治疗侵袭性癌症时是至关重要的 以TNBC的身份。该公司已使用免疫检查点成功完成了概念验证研究- 抑制物(ICI)耐药的TNBC临床前小鼠模型。结果表明，烟草花叶病毒免疫 疫苗使耐ICI的TNBC对ICI治疗敏感。SBIR直接第二阶段 请求获奖以支持进一步的IND支持临床前研究，这将促进IND与 FDA将TMV疫苗产品推向临床。以下是SBIR直接执行的具体目标 第二阶段赠款：(1)确定免疫治疗产品的最佳剂量和剂量计划，以诱导 有效的抗肿瘤免疫反应，单独和联合免疫检查点阻断治疗；(2) 评价所用免疫治疗产品在小鼠体内的安全性；以及(3)为生产GMP做准备 并为符合GMP的TMV疫苗产品建立基准。拟议的计划 代表了Metaclipse产品开发进入第一阶段临床试验的关键路径。

Abstract The worldwide incidence of breast cancer is 1.68 million. Triple-negative breast cancers (TNBC) account for ~20% of total breast cancer cases (336,000 worldwide). Annually, over 40,000 new cases of TNBC are diag- nosed in the US alone. The treatment options for TNBC patients are limited. Triple negative breast cancer (TNBC) includes breast cancers that lack estrogen receptor, progesterone receptor, and HER-2 proteins. Lack of known targets and patient-to-patient variation of target antigens make TNBC one of the most challenging cancers for developing an effective therapy. New therapies are critically needed, as TNBC is also resistant to checkpoint blockade inhibition alone. We propose to develop an immunotherapy administered in combination with checkpoint blockade to treat metastatic TNBC using an approach that is personalized, thus incorporating patient-specific neoantigens and other tumor antigens that are upregulated or altered in glycosylation pattern, such as MUC-1. Metaclipse’s immunotherapy (autologous therapeutic vaccine) consists of Tumor Membrane Vesicles (TMVs) made from patient-specific tumor tissue, which carry membrane associated tumor antigens and also antigenic epitopes derived from cytosolic proteins as MHC associated peptides. These TMVs are then directly conjugated to potent glycolipid-anchored immunostimulatory molecules (GPI-ISMs) by a novel protein transfer technology. The novelty of the proposed vaccine lies not in the use of ISMs, but in the way they are employed. This direct physical linkage of TMVs and GPI-ISMs allows for simultaneous delivery of the patient’s unique tumor antigen signature and ISMs at the vaccination site to induce a robust antitumor immune re- sponse. Since the TMV vaccine is prepared from whole tumor tissue encompassing not only patient specific variation but also all of the heterogeneity of the tumors. A key advantage of our approach is that the immuno- therapy product can be prepared within a week, which is critical during treatment of aggressive cancers such as TNBC. The company has successfully completed proof-of-concept studies using an immune checkpoint in- hibitor (ICI) resistant pre-clinical mouse model of TNBC. The results demonstrate that immunization with TMV vaccine sensitizes the ICI resistant TNBC to become responsive to ICI therapy. The SBIR direct Phase II award is requested to support further IND enabling preclinical studies, which will facilitate IND meetings with the FDA to advance the TMV vaccine product to the clinic. The following are specific aims of the SBIR direct Phase II grant: (1) determine optimal dose and dosing schedule of the immunotherapy product in inducing an effective antitumor immune response, alone and in combination with immune checkpoint blockade therapy; (2) evaluate safety of the administered immunotherapy product in mice; and (3) prepare for GMP production of human GPI-ISMs and establish benchmarks for a GMP-compliant TMV vaccine product. The proposed plan represents Metaclipse’s critical path for product development to enter into a Phase 1 clinical trial.