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 约占乳腺癌病例总数的20%（全球336，000例）。每年有超过40，000例新的TNBC病例被诊断， 在美国独自一人。TNBC患者的治疗选择有限。三阴性乳腺癌 乳腺癌（TNBC）包括缺乏雌激素受体、孕酮受体和HER-2蛋白的乳腺癌。缺乏 已知靶点的多样性和靶抗原的患者间差异使TNBC成为最具挑战性的肿瘤治疗方法之一。 癌症的有效治疗方法。迫切需要新的治疗方法，因为TNBC也耐药。 检查点阻断抑制单独。我们建议开发一种免疫疗法， 与检查点阻断治疗转移性TNBC使用的方法是个性化的，从而结合 患者特异性新抗原和糖基化模式上调或改变的其它肿瘤抗原， 例如MUC-1。Metaclipse的免疫疗法（自体治疗性疫苗）由肿瘤膜组成 由患者特异性肿瘤组织制成的囊泡（TMV），携带膜相关肿瘤抗原 以及衍生自胞质蛋白的抗原表位作为MHC相关肽。然后这些TMV 通过一种新的蛋白质直接与有效的糖脂锚定免疫刺激分子（GPI-ISM）结合 转让技术。这种疫苗的新奇不在于使用ISM，而在于它们的使用方式。 就业。TMV和GPI-ISM的这种直接物理连接允许同时递送患者的药物。 独特的肿瘤抗原特征和免疫接种部位的ISM，以诱导强大的抗肿瘤免疫反应， sponse。由于TMV疫苗是从整个肿瘤组织制备的，不仅包括患者特异性的， 变异性，以及肿瘤的所有异质性。我们的方法的一个关键优势是免疫- 治疗产品可以在一周内制备，这在治疗侵袭性癌症期间是至关重要的， 作为TNBC。该公司已经成功完成了使用免疫检查点的概念验证研究， 抑制剂（ICI）抗性TNBC临床前小鼠模型。结果表明，用TMV免疫 疫苗使ICI抗性TNBC敏感，从而变得对ICI疗法有反应。SBIR直接第二阶段 申请该奖项以支持进一步的IND临床前研究，这将促进IND会议， FDA将TMV疫苗产品推向临床。以下是SBIR直接的具体目标 II期资助：（1）确定免疫治疗产品诱导免疫应答的最佳剂量和给药方案。 有效的抗肿瘤免疫应答，单独使用和与免疫检查点阻断疗法联合使用;（2） 评价所施用的免疫治疗产品在小鼠中的安全性;和（3）准备GMP生产 人GPI-ISM并建立符合GMP TMV疫苗产品的基准。拟议计划 代表Metaclipse产品开发进入1期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.