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

• 批准号: 8930095
• 负责人: Juan fernando Vera
• 金额: $ 26.74万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 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/8930095
• 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; Metastatic breast cancer; 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; antitumor effect; 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; personalized medicine; prevent; receptor; response; safety testing; success; trafficking; treatment strategy; tumor; tumor growth; tumor microenvironment

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破坏细胞毒性T细胞免疫反应。因此，之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取得了有限的成功。相反，我们建议采用过继性转移 T 细胞，这些 T 细胞在离体工程中以肿瘤和肿瘤环境为目标，并配备了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，通过天然和嵌合受体同时靶向两种肿瘤相关抗原 Her2 和 Muc1，从而最大限度地减少抗原和 MHC 调节作为逃避 T 细胞识别的手段的影响。 2) 接下来，我们将评估这些过继转移的二元 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细胞免受恶劣肿瘤微环境的影响，我们开发了一种新型嵌合细胞因子受体（4/7R）。这种嵌合 4/7R 分子的转基因表达使工程化 T 细胞能够利用肿瘤部位产生的抑制性 Th2 细胞因子 IL4，来促进 T 细胞在体内的扩增、持久性和细胞毒活性。这些抗肿瘤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出色的药物经济学特征，因为 T 细胞治疗的临床益处可以长期持续，并且毒性最小。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拥有独特的优势，可以将拟议的研究转化为临床，因为这些中心拥有知识、经验和专业基础设施。