Membrane-based vaccine with checkpoint blockade for triple negative breast cancer

全球乳腺癌发病率为168万。三阴性乳腺癌(TNBC)约占全球乳腺癌病例总数(336,000例)的20%。每年，仅在美国就诊断出超过4万例新的TNBC病例。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。由于缺乏已知的靶点和不同患者的靶抗原差异，使得TNBC成为开发有效治疗方法的最具挑战性的癌症之一。迫切需要新的治疗方法，因为TNBC也对单独的检查点封锁抑制具有抵抗力。我们建议开发一种结合检查点阻断的免疫疗法来治疗转移性TNBC，使用一种个性化的方法，从而整合患者特有的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)由患者特定肿瘤组织制成的肿瘤膜小泡(TMV)组成，TMV携带膜相关肿瘤抗原和来自胞浆蛋白的抗原表位作为MHC相关多肽。然后通过一种新的蛋白质转移技术将这些TMV直接连接到有效的糖脂锚定的免疫刺激分子(GPI-ISM)上。提议的疫苗的新颖性不在于对ISM的使用，而在于它们的使用方式。TMV和GPI-ISM之间的这种直接物理联系允许在接种部位同时传递患者独特的肿瘤抗原信号和ISM，以诱导强大的抗肿瘤免疫反应。因为TMV疫苗是从整个肿瘤组织制备的，不仅包括患者特定的变异，而且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(如TNBC)时至关重要。该公司已经成功地完成了使用抗免疫检查点抑制剂(ICI)的TNBC临床前小鼠模型的概念验证研究。结果表明，TMV疫苗免疫使耐ICI的TNBC对ICI治疗敏感。申请SBIR DIRECT第二阶段奖是为了支持进一步的IND临床前研究，这将促进IND与FDA的会议，将TMV疫苗产品推向临床。SBIR直接第二阶段赠款的具体目标如下：(1)确定免疫治疗产品单独或与免疫检查点阻断治疗联合诱导有效抗肿瘤免疫反应的最佳剂量和剂量计划；(2)评估给予免疫治疗产品在小鼠身上的安全性；以及(3)为生产人类GPI-ism GMP做准备，并为符合GMP标准的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。

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 response. 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 inhibitor (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.