Membrane-based immunotherapy for triple negative breast cancer- a partnered approach

 描述（由申请人提供）：FDA最近批准的抗癌免疫抑制药物证实，刺激癌症患者的免疫系统是控制或预防转移性疾病的有效方法。然而，批准的免疫检查点阻断抑制剂仅在黑色素瘤患者的一个子集中有效，并且大多数癌症患者对药物没有反应。此外，乳腺癌等癌症对这些药物的反应不佳，这表明需要开发其他免疫刺激方法，如治疗性疫苗接种。开发基于疫苗的癌症免疫疗法的主要问题之一是疾病的异质性。最近的深度基因测序研究表明，肿瘤基因突变存在广泛的肿瘤内和人际异质性。因此，使用单一抗原/肽或患者来源的自体/同种异体肿瘤细胞系（其可能不代表肿瘤的异质性）开发治疗性疫苗将不会导致针对肿瘤抗原广度的免疫应答。因此，为了诱导针对患者的特异性抗原特征的免疫力，使用基于完整自体肿瘤组织的最佳佐剂化疫苗是高度期望的。我们已经开发了一种用于癌症免疫治疗的基于佐剂的全肿瘤组织的疫苗，其使用从全肿瘤组织制备的肿瘤膜囊泡（TMV），并通过使用新的蛋白质转移方法掺入免疫刺激分子（ISM）如B7-1和IL-12来修饰它们。该方法通过糖脂锚（GPI）将ISM固定到TMV上，导致TMV沿着生物佐剂同时递送到APC以增强摄取和最佳免疫细胞活化。基于有希望的小鼠临床前数据，埃默里大学和Metaclipse Therapeutics Corporation已达成协议，将这种免疫治疗方法推广到针对三阴性乳腺癌（TNBC）的诊所。这种癌症亚型具有高度异质性，靶抗原因患者而异，因此使其成为我们个性化免疫治疗的理想靶点。Metaclipse获得了NIH I期SBIR资助，以进一步验证TNBC模型中的技术，目前正在进行IND申请所需的研究。在此合作伙伴关系赠款申请中，我们建议：1）进行临床前研究以提出关于使用基于TMV的患者特异性免疫疗法与标准护理治疗组合的建议，2）研究新辅助化疗对由源自患者的异种移植物（PDX）的小鼠肿瘤组织和人肿瘤组织制备的基于TMV的免疫疗法的产量和生物活性的影响。3）在移植有人免疫系统的PDX模型中使用人TNBC肿瘤组织和人GPI-ISM评估基于TMV的免疫治疗方法。从埃默里大学和Metaclipse之间拟议的合作研究中获得的知识将有助于设计TNBC患者基于TMV的免疫疗法的临床试验策略。

 DESCRIPTION (provided by applicant): Recent approval of anti-cancer immunotherapeutic drugs by the FDA validates that stimulation of the immune system of a cancer patient is an effective way to control or prevent metastatic disease. However, the approved immune checkpoint blockade inhibitors are effective only in a subset of melanoma patients, and a majority of the cancer patients do not respond to the drugs. Moreover, cancers such as breast cancers do not respond well to these drugs, suggesting additional immune stimulatory approaches such as therapeutic vaccination need to be developed. One of the major problems in developing vaccination-based immunotherapies for cancer is the heterogeneous nature of the disease. Recent deep gene sequencing studies demonstrated extensive intratumoral and interpersonal heterogeneity in gene mutations in tumors. Therefore, developing a therapeutic vaccine using a single antigen/peptide or patient-derived autologous/allogeneic tumor cell lines, which may not represent the heterogeneity of tumors, would not result in an immune response against the breadth of tumor antigens. Therefore, to induce immunity against the specific antigenic signature of a patient, use of an optimally adjuvanted vaccine based on whole autologous tumor tissue is highly desirable. We have developed an adjuvanted whole tumor tissue based vaccine for cancer immunotherapy using tumor membrane vesicles (TMVs) prepared from whole tumor tissue and modifying them by incorporating immunostimulatory molecules (ISMs) such as B7-1 and IL-12 using a novel protein transfer method. This method immobilizes ISMs onto TMVs via a glycolipid anchor (GPI), resulting in simultaneous delivery of TMVs along with biological adjuvants to APCs for enhanced uptake and optimal immune cell activation. Based on promising preclinical data in mice, Emory University and Metaclipse Therapeutics Corporation have entered into an agreement to advance this immunotherapy approach to clinics targeting triple negative breast cancer (TNBC). This subtype of cancer is highly heterogeneous and target antigens vary from patient to patient, thus making it an ideal target for our personalized immunotherapy. Metaclipse was awarded an NIH Phase I SBIR grant to further validate the technology in a TNBC model and is currently conducting studies required for IND filing. In this partnership grant application we propose to: 1) Perform preclinica studies to make recommendations on the use of the TMV-based, patient-specific immunotherapy in combination with standard-of-care treatments, 2) Investigate the effect of neoadjuvant chemotherapy on the yield and biological activity of the TMV-based immunotherapy prepared from mouse tumor tissue and human tumor tissue derived from patient-derived xenograft (PDX) models as well as TNBC patients and 3) Evaluate the TMV-based immunotherapy approach using human TNBC tumor tissue and human GPI-ISMs in a PDX model engrafted with a human immune system. The knowledge obtained from the proposed collaborative studies between Emory University and Metaclipse will aid in designing a clinical trial strategy for TMV-based immunotherapy in TNBC patients.