Clinical Evaluation of a Personalized Vaccine Immunotherapy in Combination with Checkpoint Inhibitors for Triple Negative Breast Cancer

项目总结 三阴性乳腺癌(TNBC)是一种侵袭性乳腺癌，有效治疗方法有限。 仅在美国，每年就有超过4万例新确诊的TNBC病例。TNBC包括乳房罐头- 缺乏雌激素受体(ER)、孕激素受体(PR)和人表皮生长因子受体的CER- Tor-2(HER-2)过度表达。缺乏已知的靶点和患者对患者的靶抗原变异使 TNBC是开发有效治疗方法的最具挑战性的癌症之一。TNBC也普遍重新- 对免疫检查点抑制剂(ICI)的抵抗表明需要新的治疗方法。我们建议评估- 评价一种新的疫苗免疫疗法，单独或联合ICI治疗转移性TNBC。 Metaclipse的免疫疗法(自体治疗性疫苗)由肿瘤膜小泡(TMvs)组成 由患者特定的肿瘤组织制成，携带包括膜相关蛋白在内的肿瘤抗原 和碳水化合物抗原，以及来源于胞浆蛋白的抗原肽，作为MHC相关肽- 潮汐。这些TMV然后直接连接到有效的糖脂锚定的免疫刺激分子上 (GPI-ISMS)通过一种新的蛋白质转移技术。提议的疫苗的新颖性不在于使用 主义，而是他们的雇佣方式。TMV和GPI-ISM之间的这种直接物理联系允许同时- 在接种部位注射患者独特的肿瘤抗原标记和ISM，以诱导RO-RO。 增强抗肿瘤免疫反应。由于TMV疫苗是从整个肿瘤组织制备的，因此它可以- 不仅传递患者特定的变异，而且传递肿瘤的所有异质性。我们的一个主要优势是 方法是免疫治疗产品可以在不到14天的时间内制备好，这在 治疗侵袭性癌症，如TNBC。该公司已成功完成临床前研究 使用抗ICI的临床前小鼠模型，包括TNBC。结果表明，免疫接种 TMV疫苗使耐ICI的4T1 TNBC对ICI治疗敏感。此外，GLP毒素- 在小鼠身上的生理学研究证明了疫苗的安全性，即使在5倍剂量的情况下与ICI疗法联合使用也是如此。 APY。此外，我们还建立了：(1)稳定表达人cGMP的CHO细胞克隆 GPI蛋白，(2)用于生产和纯化符合cGMP的GPI锚定蛋白的SOP，以及 (3)用于加工人TNBC肿瘤样本以生产TMV疫苗的SOP。SBIR Direct 第二阶段的提案旨在将这项技术转化为临床应用。以下具体目标涉及 该提案的总体目标：(1)cGMP药品的制造；(2)1a/b期临床试验-ES- 建立安全性和免疫反应，以及疫苗单独和联合免疫效果的初步迹象 与免疫检查点抑制剂(ICI)联合使用。提议的计划代表了Metaclipse的关键路径 启动并完成1a/b期临床试验。这些目标的成功实现将推动我们独特的 个性化疫苗免疫治疗平台更接近于治疗目前没有效果的TNBC患者- 由于疾病的高度异质性，有多种有效的治疗方案。

PROJECT SUMMARY Triple negative breast cancer (TNBC) is an aggressive type of breast cancer with limited effective therapies. Each year more than 40,000 new cases of TNBC are diagnosed in the US alone. TNBC includes breast can- cers that lack estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor recep- tor 2 (HER-2) overexpression. 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. TNBC is also generally re- sistant to the immune checkpoint inhibitors (ICI) suggesting the need for novel therapies. We propose to eval- uate a novel vaccine immunotherapy administered alone or in combination with ICI to treat metastatic TNBC. Metaclipse’s immunotherapy (autologous therapeutic vaccine) consists of tumor membrane vesicles (TMVs) made from patient-specific tumor tissue, which carry tumor antigens including membrane-associated protein and carbohydrate antigens, and antigenic peptides derived from cytosolic proteins as MHC-associated pep- tides. 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 the way they are employed. This direct physical linkage of TMVs and GPI-ISMs allows for simulta- neous delivery of the patient’s unique tumor antigen signature and ISMs at the vaccination site to induce a ro- bust anti-tumor immune response. Since the TMV vaccine is prepared from whole tumor tissue, it encom- passes not only patient-specific variation but also all of the heterogeneity of the tumors. A key advantage of our approach is that the immunotherapy product can be prepared in less than 14 days, which is critical during treatment of aggressive cancers such as TNBC. The company has successfully completed preclinical studies using ICI-resistant preclinical mouse models including TNBC. The results demonstrate that immunization with TMV vaccine sensitizes the ICI-resistant 4T1 TNBC to become responsive to ICI therapy. In addition, GLP tox- icology studies in mice demonstrated the safety of the vaccine, even at a 5X dose in combination with ICI ther- apy. Furthermore, we have established: (1) stable cGMP-compliant CHO cell clones expressing the human GPI-proteins, (2) SOPs for the cGMP-compliant production and purification of the GPI-anchored proteins, and (3) SOPs for processing of samples from human TNBC tumors to generate TMV vaccine. The SBIR Direct Phase II proposal is aimed at translating this technology to the clinic. The following specific aims address the overall goals of the proposal: (1) cGMP manufacturing of drug substance; (2) a phase 1a/b clinical trial to es- tablish safety and immune response, as well as preliminary indication of efficacy of the vaccine alone and in combination with immune checkpoint inhibitors (ICI). The proposed plan represents Metaclipse’s critical path to initiate and complete a phase 1a/b clinical trial. Successful completion of these aims will advance our unique personalized vaccine immunotherapy platform closer to treating TNBC patients who currently do not have ef- fective treatment options due to the highly heterogenous nature of the disease.