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

个性化疫苗免疫疗法联合检查点抑制剂治疗三阴性乳腺癌的临床评价

• 批准号: 10489848
• 负责人: CHRISTOPHER D PACK
• 金额: $ 93.86万
• 依托单位: METACLIPSE THERAPEUTICS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-16 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10489848
• 关键词: 4T1; Address; Affinity Chromatography; Antibodies; Antigen Targeting; Antigens; Antitumor Response; Autologous; Award; Benchmarking; Biological; Biological Assay; Bioreactors; Blood; Breast Cancer Patient; CD8-Positive T-Lymphocytes; CD80 gene; Cancer Vaccines; Carbohydrates; Cell Line; Chinese Hamster Ovary Cell; Clinic; Clinical; Clinical Trials; Clone Cells; Critical Pathways; Cyclic GMP; Dendritic Cells; Development; Disease; Dose; ERBB2 gene; Enrollment; Epidermal Growth Factor Receptor; Estrogen Receptors; Foundations; Freezing; Funding; Gene Transfer; Glycolipids; Goals; Heterogeneity; Human; Immune; Immune checkpoint inhibitor; Immune response; Immunity; Immunization; Immunotherapy; Interferons; Interleukin-12; Laboratory culture; Licensing; Logistics; Malignant Neoplasms; Maximum Tolerated Dose; Membrane; Membrane Proteins; Methods; Mus; Nature; Neoplasm Metastasis; Particulate; Patients; Peptides; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Phase Ia Clinical Trial; Phase Ib Trial; Physiologic pulse; Procedures; Production; Progesterone Receptors; Prognosis; Progression-Free Survivals; Proteins; Quality Control; Regimen; Reproducibility; Research; Resistance; Running; Safety; Sampling; Scheme; Site; Small Business Innovation Research Grant; Technology; Technology Transfer; Testing; Therapeutic; Time; Tissues; Toxicology; Translating; Tumor Antigens; Tumor Tissue; Vaccination; Vaccine Clinical Trial; Vaccine Production; Vaccines; Variant; Vesicle; anti-CTLA4 antibodies; anti-PD1 antibodies; anti-tumor immune response; arm; breast cancer diagnosis; checkpoint therapy; chemokine; cohort; cost effective; cytokine; design; disorder control; dosage; effective therapy; enzyme linked immunospot assay; established cell line; malignant breast neoplasm; meetings; mouse model; novel; novel therapeutics; novel vaccines; open label; overexpression; patient variability; personalized immunotherapy; pre-clinical; preclinical study; primary endpoint; programmed cell death ligand 1; protein purification; receptor; refractory cancer; research clinical testing; response; scale up; secondary endpoint; sterility testing; targeted treatment; therapeutic vaccine; triple-negative invasive breast carcinoma; tumor; tumor heterogeneity; vaccine efficacy; vaccine immunotherapy; vaccine safety

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.

项目概要 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 40,000 例新诊断的 TNBC 病例，其中包括乳腺癌。 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细胞 tor 2 (HER-2) 过度表达的缺乏以及患者与患者之间的靶抗原存在差异。 TNBC 是开发有效疗法最具挑战性的癌症之一，通常也需要重新治疗。 对免疫检查点抑制剂（ICI）的抵抗表明需要新的疗法。 我们开发了一种单独或与 ICI 联合施用的新型疫苗免疫疗法来治疗转移性 TNBC。 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，携带包括膜相关蛋白在内的肿瘤抗原 和碳水化合物抗原，以及源自胞质蛋白的抗原肽，作为 MHC 相关的 pep- 然后这些 TMV 直接与有效的糖脂锚定免疫刺激分子结合。 （GPI-ISM）通过新型蛋白质转移技术提出的疫苗的新颖性不在于使用。 ISM，但 TMV 和 GPI-ISM 的这种直接物理连接方式允许同时进行。 在疫苗接种地点新鲜递送患者独特的肿瘤抗原特征和 ISM，以诱导 由于 TMV 疫苗是由整个肿瘤组织制备的，因此它可以抑制抗肿瘤免疫反应。 不仅通过了患者特异性变异，还通过了肿瘤的所有异质性，这是我们的一个关键优势。 方法是可以在不到14天的时间内制备出免疫治疗产品，这在过程中至关重要 该公司已成功完成 TNBC 等侵袭性癌症的治疗临床前研究。 使用包括 TNBC 在内的 ICI 抗性临床前小鼠模型，结果表明免疫接种。 TMV 疫苗使 ICI 耐药的 4T1 TNBC 变得敏感，从而对 ICI 治疗产生反应。此外，GLP 毒 - 对小鼠进行的免疫学研究证明了该疫苗的安全性，即使是与 ICI 热疗法联合使用 5 倍剂量时也是如此。 此外，我们还建立了：（1）表达人类的稳定的符合 cGMP 的 CHO 细胞克隆。 GPI 蛋白，(2) 用于符合 cGMP 生产和纯化 GPI 锚定蛋白的 SOP，以及 (3) 用于处理人类 TNBC 肿瘤样本以生成 TMV 疫苗的 SOP。 第二阶段提案旨在将该技术转化为临床，以下具体目标旨在解决以下问题。 该提案的总体目标：(1) 原料药的 cGMP 生产；(2) es-的 1a/b 期临床试验 建立安全性和免疫反应，以及单独疫苗和联合疫苗功效的初步指示 与免疫检查点抑制剂（ICI）的结合所提出的计划代表了 Metaclipse 的关键路径。 启动并完成 1a/b 期临床试验的成功完成将推进我们独特的目标。 个性化疫苗免疫治疗平台更接近于治疗目前尚无疗效的 TNBC 患者 由于疾病的高度异质性，有效的治疗方案。