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

项目摘要 三阴性乳腺癌（TNBC）是一种侵袭性类型的乳腺癌，有效疗法有限。 仅在美国，每年就有超过40，000例新的TNBC病例被诊断出来。TNBC包括乳腺癌- 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cers， TOR 2（HER-2）过表达。缺乏已知的靶点和靶抗原的患者间变异使得 TNBC是开发有效疗法最具挑战性的癌症之一。TNBC通常也会重新- 对免疫检查点抑制剂（ICI）有抵抗力，这表明需要新的治疗方法。我们建议评估- 评估单独或与ICI联合施用以治疗转移性TNBC的新型疫苗免疫疗法。 Metaclipse的免疫疗法（自体治疗性疫苗）由肿瘤膜囊泡（TMV）组成， 由患者特异性肿瘤组织制成，其携带包括膜相关蛋白的肿瘤抗原 和碳水化合物抗原，以及衍生自胞质蛋白的抗原肽，如MHC相关的pep- 潮汐然后将这些TMV直接与有效的糖脂锚定免疫刺激分子结合 （GPI-ISMs）通过一种新的蛋白质转移技术。这种疫苗的新奇不在于使用 但他们的工作方式。TMV和GPI-ISM的这种直接物理连接允许同时 在疫苗接种部位新递送患者独特的肿瘤抗原标记和ISM，以诱导免疫应答。 破坏抗肿瘤免疫反应。由于TMV疫苗是从整个肿瘤组织制备的，它包括- 不仅通过了患者特异性变异，还通过了肿瘤的所有异质性。我们的一个关键优势是 免疫治疗产品可以在不到14天的时间内制备，这在治疗过程中至关重要。 治疗侵袭性癌症，如TNBC。该公司已成功完成临床前研究 使用ICI抗性临床前小鼠模型，包括TNBC。结果表明，用 TMV疫苗使ICI抗性4 T1 TNBC敏感，从而对ICI疗法产生响应。此外，GLP毒性- 在小鼠中的免疫学研究证明了疫苗的安全性，即使在5倍剂量下与ICI疗法联合使用， - 是的此外，我们还建立了：（1）稳定的cGMP-顺应性CHO细胞克隆，表达人 （2）用于GPI锚定蛋白的cGMP合规生产和纯化的SOP，和 (3)用于处理来自人TNBC肿瘤的样品以生成TMV疫苗的SOP。SBIR Direct 第二阶段的建议旨在将这项技术转化为临床。以下具体目标涉及 该提案的总体目标：（1）原料药的cGMP生产;（2）1a/B期临床试验， 建立安全性和免疫应答，以及疫苗单独和 与免疫检查点抑制剂（ICI）组合。拟议的计划代表了Metaclipse的关键路径， 启动并完成1a/B期临床试验。成功实现这些目标将推动我们独特的 个性化疫苗免疫治疗平台更接近于治疗目前没有疗效的TNBC患者， 有效的治疗选择，因为疾病的高度异质性。

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.