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

乳腺癌及其微环境可直接破坏细胞毒性T细胞免疫反应。因此，以前通过疫苗接种诱导细胞介导的体内抗肿瘤反应的努力取得了有限的成功。我们建议采用过继性转移T细胞，这些T细胞经过体外工程改造，以靶向肿瘤和肿瘤环境，并配备了针对有效肿瘤免疫逃避策略的对策。在这个应用中，我们建议：1)通过天然受体和嵌合受体产生双特异性T细胞，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性转移的二元T细胞在难治性乳腺癌患者中的安全性和功能。3)最后，为了保护这些体外生成的双特异性T细胞免受恶性肿瘤微环境的侵害，我们开发了一种新的嵌合细胞因子受体（4/7R）。这种嵌合4/7R分子的转基因表达允许工程T细胞利用在肿瘤部位产生的抑制性Th2细胞因子IL4来促进T细胞在体内的增殖、持久性和细胞毒性活性。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试验。我们的方法具有潜在的突出的药物经济学特征，因为T细胞治疗的临床益处可以长期持续，并且应该与最小的毒性相关。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具有独特的定位，可以将这些中心所拥有的知识、经验和专业基础设施转化为临床研究。

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.