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

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，以前通过接种疫苗在体内诱导细胞介导的抗肿瘤反应的努力取得的成功有限。相反，我们建议过继转移体外工程的T细胞，以靶向肿瘤和肿瘤环境，并配备有效的肿瘤免疫逃避策略的对策。在这一应用中，我们建议：1)产生双特异性T细胞，通过天然和嵌合受体同时靶向两个肿瘤相关抗原Her2和MUC1，从而将抗原和MHC调节作为逃避T细胞识别的手段的影响降至最低。2)接下来，我们将评估这些过继转移的二进制T细胞在难治性乳腺癌患者中的安全性和功能。3)最后，为了保护这些体外产生的双特异性T细胞免受恶性肿瘤微环境的影响，我们开发了一种新的嵌合细胞因子受体(4/7R)。这种嵌合的4/7R分子的转基因表达使工程T细胞能够利用肿瘤部位产生的抑制性Th2细胞因子IL4，而不是促进T细胞在体内的扩张、持久性和细胞毒活性。这些抗癌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突出的药物经济学特征，因为临床上T细胞治疗的好处可以长期持续，并且应该与最小的毒性相关。鉴于细胞和基因治疗中心(CAGT)和德克萨斯医学中心的乳腺癌中心拥有的知识、经验和专业基础设施，这些中心在将拟议的研究转化为临床方面具有独特的地位。

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.