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

 描述(申请人提供)：FDA最近批准的抗癌免疫治疗药物证实，刺激癌症患者的免疫系统是控制或预防转移疾病的有效方法。然而，批准的免疫检查点阻断抑制剂只对一小部分黑色素瘤患者有效，而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。最近深入的基因测序研究表明，肿瘤中的基因突变具有广泛的瘤内和人际异质性。因此，开发一种使用单一抗原/多肽或患者来源的自体/同种异体肿瘤细胞系的治疗性疫苗，可能不代表肿瘤的异质性，不会导致对多种肿瘤抗原的免疫反应。因此，为了诱导针对患者特异性抗原特征的免疫，基于整个自体肿瘤组织的最佳佐剂疫苗的使用是非常可取的。我们利用从整个肿瘤组织制备的肿瘤膜小泡(TMV)，并通过引入免疫刺激分子(ISM)，如B7-1和IL-12，利用一种新的蛋白质转移方法，开发了一种基于全肿瘤组织的佐剂肿瘤免疫治疗疫苗。这种方法通过糖脂锚(GPI)将TMV固定在TMV上，导致TMV与生物佐剂同时输送到APC，以增强摄取和最佳免疫细胞激活。基于有希望的小鼠临床前数据，埃默里大学和Metaclipse治疗公司达成了一项协议，将这种免疫治疗方法推广到针对三阴性乳腺癌(TNBC)的临床。这种癌症亚型具有高度的异质性，不同患者的靶抗原不同，因此它是我们个性化免疫治疗的理想靶点。Metaclipse获得了NIH第一阶段SBIR赠款，以进一步在TNBC模型中验证这项技术，目前正在进行IND申报所需的研究。在这项合作伙伴关系赠款申请中，我们建议：1)进行临床前研究，就结合标准护理治疗使用基于TMV的患者特异性免疫治疗提出建议；2)调查新辅助化疗对从患者衍生异种移植(PDX)模型以及TNBC患者的小鼠肿瘤组织和人类肿瘤组织制备的基于TMV的免疫治疗的产量和生物活性的影响；3)在移植了人类免疫系统的PDX模型中，使用人TNBC肿瘤组织和人GPI来评估基于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为TNBC患者设计基于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.