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

基于膜的三阴性乳腺癌免疫疗法——一种合作方法

基本信息

批准号：
9895637
负责人：
CHRISTOPHER D PACK
金额：
$ 48.09万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9895637
关键词：
4T1 Address Adjuvant Affect Agreement Aliquot Allogenic Antigen Targeting Antigens Applications Grants Area Autologous Award Biological Biological Response Modifier Therapy Biological Sciences Breast Cancer Model Breast Cancer Patient CD34 gene CD80 gene Cancer Patient Cancer Vaccines Cells Clinic Clinical Protocols Clinical Trials Data Development Disease ERBB2 gene Estrogen Receptors Excision Freezing Future Gene Mutation Gene Transfer Genes Globo-H Glycolipids Grant Heterogeneity Human Immobilization Immune Immune response Immune system Immunity Immunization Immunodeficient Mouse Immunotherapy Implant Injections Interleukin-12 Knowledge Liver Malignant Neoplasms Medical Membrane Methods Modeling Mucins Mus Nature Neoadjuvant Therapy Neoplasm Metastasis Operative Surgical Procedures Patients Peptides Pharmaceutical Preparations Phase Preparation Prior Chemotherapy Process Progesterone Receptors Property Proteins Recommendation Research Personnel Small Business Innovation Research Grant Surface Antigens System Technology Technology Transfer Testing Therapeutic Thymus Gland Translating Tumor Antigens Tumor Cell Line Tumor Tissue Tumor-Derived Tumor-infiltrating immune cells United States National Institutes of Health Universities Vaccination Vaccine Adjuvant Vaccine Therapy Vaccines Vesicle Xenograft Model Xenograft procedure anti-cancer anti-tumor immune response base cancer immunotherapeutics cancer immunotherapy cancer subtypes chemotherapy cost cost effective cytokine design effective therapy efficacy testing established cell line humanized mouse immune activation immune checkpoint blockade inhibitor/antagonist malignant breast neoplasm melanoma mouse model novel novel therapeutics outcome forecast overexpression patient variability personalized immunotherapy pre-clinical preclinical study prevent public health relevance reconstitution small molecule therapeutics standard of care therapeutic evaluation therapeutic target therapeutic vaccine triple-negative invasive breast carcinoma tumor tumor heterogeneity tumor xenograft uptake

项目摘要

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.

描述（由适用提供）：通过FDA近期批准抗癌免疫治疗药物，证明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。但是，经批准的免疫障碍抑制剂仅在黑色素瘤患者的一部分中有效，大多数癌症患者对药物没有反应。此外，诸如乳腺癌患者之类的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，例如治疗疫苗。开发癌症免疫疗法的主要问题之一是该疾病的异质性质。最近的深基因测序研究表明，肿瘤基因突变中广泛的肿瘤内和人际异质性。因此，使用单个抗原/肽或患者衍生的自体/同种异体肿瘤细胞系（可能不能代表肿瘤的异质性）开发治疗性疫苗不会导致针对肿瘤抗原宽的免疫响应。因此，为了诱导患者的免疫组织性特征，基于整个自体肿瘤组织的最佳调整疫苗是非常可取的。我们已经使用了从整个肿瘤组织制备的肿瘤膜蔬菜（TMV）开发了一种调整后的肿瘤组织疫苗，用于癌症免疫疗法，并通过使用新颖的蛋白质转移方法掺入诸如B7-1和IL-12的免疫刺激分子（ISMS）（例如B7-1和IL-12）来修饰它们。这种方法通过糖脂锚（GPI）将ISMS固定在TMV上，从而使TMV以及生物调节器简单地递送到APC中，以增强摄取和最佳的免疫电池活化。基于小鼠的有前途的临床前数据，埃默里大学和Metaclipse Therapeutics Corporation已达成一项协议，以推进针对三重阴性乳腺癌（TNBC）的诊所的这种免疫疗法方法。这种癌症的亚型是高度异质性的，靶向抗原因患者而异，因此成为我们个性化免疫疗法的理想目标。 MetaClipse被授予NIH I期SBIR赠款，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。在本合作授予的应用中，我们建议：1）进行临时林卡研究，以提出有关使用基于TMV的，患者特异性免疫疗法与护理标准治疗联合使用的建议，2）研究新辅助化学疗法对Neoadjuvant化学疗法对TMV的产量和生物学疗法的产生和生物学疗法的影响。 TNBC患者和3）在植入人类免疫系统的PDX模型中，使用人类TNBC肿瘤组织和人类GPI-SISM评估基于TMV的免疫疗法方法。从Emory大学和Metaclipse之间提出的合作研究中获得的知识将有助于设计基于TMV的TNBC患者的临床试验策略。