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: 10551635
• 负责人: CHRISTOPHER D PACK
• 金额: $ 3.46万
• 依托单位: METACLIPSE THERAPEUTICS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10551635
• 关键词: Address; Affect; Antigens; Autologous; Breast Cancer Patient; CD80 gene; Cancer Model; Cancer Patient; Cancer Vaccines; Charge; Clinical Trials; Data; ERBB2 gene; Estrogen Receptors; Excision; Exclusion Criteria; Future; Glycolipids; Grant; Heterogeneity; Human; Immune Targeting; Immune checkpoint inhibitor; Immunity; Interleukin-12; Knowledge; Lymphocyte; Malignant Neoplasms; Membrane; Methods; Neoadjuvant Therapy; Neoplasm Metastasis; Operative Surgical Procedures; Patient Selection; Patients; Phase I Clinical Trials; Phase II Clinical Trials; Physiologic pulse; Progesterone Receptors; Prognosis; Proteins; Resistance; T-Cell Activation; T-Lymphocyte; Therapeutic; Time; Treatment Protocols; Tumor Tissue; Vaccines; Vesicle; Woman; base; checkpoint therapy; chemotherapy; cost effective; design; effective therapy; inclusion criteria; malignant breast neoplasm; mortality; mouse model; neoplastic cell; novel; parent grant; protein biomarkers; protein expression; receptor; research clinical testing; standard of care; triple-negative invasive breast carcinoma; tumor; vaccine development; vaccine immunotherapy

Abstract of the supplemental grant: Breast cancer accounts for the highest cancer-related mortality in women. Among its subtypes, metastatic triple negative breast cancer (TNBC) has the worst prognosis largely due to resistance to currently available therapies and lack of estrogen receptor, progesterone receptor and HER-2 protein expression. Recent studies employing immune checkpoint inhibitor (ICI) therapies suggest that TNBC may be a good target for ICI therapy due to the presence of high level of infiltrating lymphocytes. However, the majority of the TNBC cancer patients do not respond to ICI therapy due to the lack of pre-existing immunity. In order to develop more effective treatments, it is important to design a therapeutic approach for TNBC patients which overcomes intra-tumoral and inter-patient heterogeneity. Metaclipse Therapeutics has been engaged in developing a personalized vaccine to address heterogeneity. Utilizing a novel protein transfer method, we generate tumor membrane vesicles (TMVs) derived from whole tumor tissues and modify them with glycolipid-anchored forms of immunostimulatory molecules (GPI- ISMs) expressing B7-1 and interleukin-12 (IL-12). Our data demonstrates that TMV vaccines prepared from syngeneic tumors are effective in multiple murine models of cancer. However, it is currently unknown if neoadjuvant chemotherapy which is a standard of care for breast cancer affects the yield and quality of TMV- based vaccines. We hypothesize that the addition of standard-of-care (SOC) chemotherapy which is usually administered in TNBC patients before surgery impacts the yield and quality of TMV-based vaccines. To address this, the following specific aims are proposed. Aim 1, To define the impact of neoadjuvant chemotherapy on the yield and quality of the TMV vaccine. Aim 2, To define the impact of neoadjuvant chemotherapy on the ability of TMV vaccine to stimulate APCs and autologous T cells ex vivo. The parent grant of this supplement proposal will be conducting Phase 1 clinical trial to evaluate the tolerability of TMV vaccine in TNBC patients. This study will provide an understanding about how the neoadjuvant chemotherapy impacts the TMV-based vaccines prepared from TNBC tumors.

补充补助金摘要： 乳腺癌是女性癌症相关死亡率最高的癌症。在其亚型中，转移性三联 阴性乳腺癌 (TNBC) 的预后最差，很大程度上是由于对当前可用疗法的耐药性 且缺乏雌激素受体、孕激素受体和HER-2蛋白表达。最近的研究采用 免疫检查点抑制剂（ICI）疗法表明，TNBC 可能是 ICI 治疗的良好靶点，因为 存在高水平的浸润淋巴细胞。然而，大多数 TNBC 癌症患者并不 由于缺乏预先存在的免疫力，对 ICI 治疗有反应。为了开发更有效的治疗方法， 为 TNBC 患者设计一种克服肿瘤内和患者间治疗方法的治疗方法非常重要 异质性。 Metaclipse Therapeutics 一直致力于开发一种个性化疫苗来解决 异质性。利用一种新颖的蛋白质转移方法，我们生成了源自肿瘤膜囊泡（TMV）的肿瘤膜囊泡（TMV） 从整个肿瘤组织中提取并用糖脂锚定形式的免疫刺激分子（GPI- ISM）表达 B7-1 和白细胞介素 12 (IL-12)。我们的数据表明，TMV 疫苗是由 同基因肿瘤对多种小鼠癌症模型有效。但目前尚不清楚是否 作为乳腺癌护理标准的新辅助化疗会影响 TMV 的产量和质量 为基础的疫苗。我们假设添加标准护理（SOC）化疗（通常是 TNBC 患者在手术前接种会影响基于 TMV 的疫苗的产量和质量。致地址 为此，提出以下具体目标。目标 1，明确新辅助化疗对 TMV 疫苗的产量和质量。目标 2，明确新辅助化疗对患者能力的影响 TMV 疫苗可离体刺激 APC 和自体 T 细胞。本补充提案的家长补助金 将进行一期临床试验，以评估 TMV 疫苗在 TNBC 患者中的耐受性。这项研究 将帮助人们了解新辅助化疗如何影响基于 TMV 的疫苗 由 TNBC 肿瘤制备。