Evading Immune Escape Mechanisms in Dual-Targeted T-cell Therapy for Breast Canc

乳腺癌双靶点 T 细胞治疗中规避免疫逃逸机制

基本信息

批准号：
8747145
负责人：
Juan fernando Vera
金额：
$ 26.39万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8747145
关键词：
Adoptive Transfer Antibodies Antigen Targeting Antigens Breast Breast Cancer Cell Bulky Disease Cancer Center Cell Therapy Cell surface Cells Clinic Clinical Clinical Protocols Clinical Research Clinical Trials Collaborations Cytokine Receptor Binding Cytokine Receptors Cytotoxic T-Lymphocytes Data Development Distant Economics Effector Cell Engineering Environment Genetic Goals Hodgkin Disease IL4 gene IL7 gene Immune Immune Targeting Immune response Immune system Immunosuppressive Agents Immunotherapeutic agent Infusion procedures Interleukin 4 Receptor Interleukin 7 Receptor Knowledge MHC antigen Malignant Neoplasms Measures Mediating Medical center Modeling Modification Mus Nasopharynx Carcinoma Neuroblastoma Outcome Patients Phase Positioning Attribute Pre-Clinical Model Production Recurrence Refractory Research Infrastructure Resistance Risk Safety Signal Transduction Site Staging T cell therapy T-Lymphocyte Testing Texas Therapeutic Time Toxic effect Transgenic Organisms Translating Translational Research Translations Trastuzumab Tumor Antigens Tumor Escape Tumor-Derived Vaccination Vaccines arm base cancer cell cellular engineering chimeric antigen receptor conventional therapy cytokine cytotoxic effective therapy experience fighting gene therapy immunogenic improved in vitro activity in vivo killer T cell malignant breast neoplasm melanoma neoplastic cell novel prevent receptor response safety testing success trafficking treatment strategy tumor tumor growth tumor microenvironment

项目摘要

Breast cancer and its microenvironment can directly subvert cytotoxic T cell immune responses. Thus, previous efforts to induce cell-mediated anti-tumor responses in vivo by vaccination have had limited success. We propose instead to adoptively transfer T cells that are engineered ex vivo to target the tumor and the tumor environment, and are armed with countermeasures to a potent tumor immune evasion strategy. In this application we propose to: 1) generate bi-specific T cells that simultaneously target two tumor-associated antigens, Her2 and Muc1, through native and chimeric receptors, thereby minimizing the impact of antigen and MHC modulation as a means of evading T cell recognition. 2) Next, we will assess the safety and function of these adoptively-transferred binary T cells in patients with refractory breast cancer. 3) Finally, to protect these ex vivo generated bi-specific T cells from the hostile tumor microenvironment, we have developed a novel chimeric cytokine receptor (4/7R). Transgenic expression of this chimeric 4/7R molecule allows the engineered T cells to utilize the suppressive Th2 cytokine IL4, produced at the tumor site, to instead promote the T cells' expansion, persistence, and cytotoxic activity in vivo. The safety and anti-tumor activity of these tumor-resistant T cells will be tested clinically in patients with metastatic breast cancer. Our approach has a potentially outstanding pharmaco-economic profile since the clinical the benefits of T cell therapy can be sustained long-term, and should be associated with minimal toxicities. The Center for Cell and Gene Therapy (CAGT), and the Breast Cancer Center at Texas Medical Center are uniquely positioned to translate to the clinic the proposed studies given the knowledge, experience, and specialized infrastructure possessed by these centers.

乳腺癌及其微环境可以直接颠覆细胞毒性T细胞免疫反应。因此，以前通过疫苗接种在体内诱导细胞介导的抗肿瘤反应的努力的成功有限。相反，我们建议通过经过体内设计的T细胞来靶向肿瘤和肿瘤环境，并配备与有效的肿瘤免疫逃避策略的对策。在此应用中，我们建议：1）生成双特异性T细胞，该细胞通过天然和嵌合受体同时靶向两种肿瘤相关的抗原HER2和MUC1，从而最大程度地减少了抗原和MHC调节的影响，作为逃避T T细胞识别的一种手段。 2）接下来，我们将评估这些经过转移的二元T细胞在难治性乳腺癌患者中的安全性和功能。 3）最后，为了保护这些离体产生的双特异性T细胞免受敌对肿瘤微环境的影响，我们开发了一种新型的嵌合细胞因子受体（4/7R）。该嵌合4/7R分子的转基因表达使工程的T细胞能够利用在肿瘤部位产生的抑制性TH2细胞因子IL4，以促进T细胞在体内的膨胀，持久性和细胞毒性活性。这些耐肿瘤T细胞的安全性和抗肿瘤活性将在转移性乳腺癌患者中进行临床测试。我们的方法具有潜在的杰出药物经济特征，因为临床T细胞疗法的益处可以长期持续，并且应与最少的毒性有关。细胞和基因治疗中心（CAGT）以及德克萨斯医学中心的乳腺癌中心独特地将这些中心拥有的知识，经验和专业基础设施转化为临床。