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

全世界乳腺癌的发病率是168万。三阴性乳腺癌（TNBC）约占乳腺癌总病例的20%（全球33.6万例）。每年，仅在美国就诊断出超过40,000例新的TNBC病例。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靶抗原在患者之间的差异，使得三阴癌成为开发有效治疗方法最具挑战性的癌症之一。目前迫切需要新的治疗方法，因为TNBC对检查点阻断抑制也有耐药性。我们建议开发一种结合检查点阻断的免疫疗法，使用一种个性化的方法来治疗转移性TNBC，从而结合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）包括由患者特异性肿瘤组织制成的肿瘤膜囊泡（tmv），其携带膜相关肿瘤抗原和来自细胞质蛋白的抗原表位，作为MHC相关肽。然后通过一种新的蛋白质转移技术将这些tmv直接结合到有效的糖脂锚定免疫刺激分子（GPI-ISMs）上。拟议疫苗的新颖之处不在于ISMs的使用，而在于它们的使用方式。tmv和GPI-ISMs的这种直接物理联系允许在接种部位同时递送患者独特的肿瘤抗原标记和ISMs，以诱导强大的抗肿瘤免疫反应。由于TMV疫苗是由整个肿瘤组织制备的，不仅包括患者的特异性变异，还包括肿瘤的所有异质性。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）期间是至关重要的。该公司已经成功完成了使用免疫检查点抑制剂（ICI）耐药的TNBC临床前小鼠模型的概念验证研究。结果表明，接种TMV疫苗可使耐ICI的TNBC增敏，使其对ICI治疗产生反应。SBIR直接II期奖励被要求支持进一步的IND临床前研究，这将促进IND与FDA的会议，以推进TMV疫苗产品的临床应用。以下是SBIR直接II期批准的具体目标：(1)确定免疫治疗产品的最佳剂量和给药计划，以诱导有效的抗肿瘤免疫反应，单独或与免疫检查点阻断疗法联合使用；(2)评价所给免疫治疗产品在小鼠体内的安全性；(3)为人GPI-ISMs的GMP生产做准备，并建立符合GMP的TMV疫苗产品的基准。拟议的计划代表了Metaclipse产品开发进入1期临床试验的关键途径。

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.