Synthetically Reengineered T cells as the Next Generation of Smart Cancer Therapy

描述（由申请人提供）：癌症是一种致命的疾病，在患者体内和患者之间存在高度的细胞异质性。目前的治疗剂并没有被设计成对抗这种异质性，这最终导致更高的耐药性和复发机会。因此，智能癌症治疗应该是特异性的，但能够解决癌细胞显示的患者内和患者间的多样性。工程化T细胞是作为这种智能疗法的理想候选者。它们可以通过基因重组来检测疾病特异性信号，做出复杂的决定，执行适当的反应，并发育成记忆T细胞。这些特性很难（如果不是不可能的话）被设计成传统的治疗剂，如小分子和抗体。最近的研究表明，患者的T细胞可以被修饰以表达癌症特异性受体，并通过过继转移回同一患者，治疗各种癌症。我们以前在T细胞中工程化信号控制电路的工作表明，T细胞可以进行高水平的遗传重编程。总之，这些结果说明了使用T细胞作为智能疗法的潜力。在这里，我们建议开发下一代基于T细胞的癌症疗法，以直接解决癌症异质性。我们将利用我们在合成基因电路和T细胞工程方面的专业知识，在T细胞中开发新的基因网络，控制何时，何地以及表达哪些癌症特异性受体，从而重新编程癌症杀伤T细胞的空间和时间活性。我们的第一类合成基因网络将通过控制 基于个体患者对过继治疗的反应，体内工程化T细胞依赖于作为网络触发器的小分子的施用。我们的第二类基因网络将通过靶向特定癌症抗原的受体将T细胞导向肿瘤，然后在确定的时间内非选择性地杀死周围的肿瘤细胞，从而对抗患者体内的异质性。这允许同时消除许多癌细胞类型，而不会引起全身毒性。这一提议的成功将导致范式转变疗法具有前所未有的灵活性，精确性和个性化。由此产生的工程化T细胞将是有史以来开发的最复杂的治疗剂。此外，这里开发的遗传电路和设计原理将作为一个通用平台，可以与任何肿瘤特异性受体结合，并补充现有的过继性T细胞治疗，因此这项工作将对许多癌症产生直接和广泛的影响。通过将两个新兴的科学领域--基于细胞的免疫疗法和合成生物学--引入癌症研究，这项提议的结果将从根本上改变癌症治疗。

DESCRIPTION (provided by applicant): Cancer is a deadly disease that is complicated by a high degree of cellular heterogeneity, both within a patient and between patients. Current therapeutic agents are not designed to combat such heterogeneity, which ultimately leads to a higher chance of drug resistance and relapse. Smart cancer therapy should therefore be specific, yet able to tackle the intra- and inter-patient diversity displayed by cancerous cells. Engineered T cells are ideal candidates to serve as such smart therapeutics. They can be genetically reprogrammed to detect disease-specific signals, make complex decisions, execute proper responses, and developed into memory T cells. These properties are very difficult, if not impossible, to engineer into traditional therapeutic agents, like small molecules and antibodies. Recent works have shown that patients' T cells can be modified to express a cancer-specific receptor ex vivo and, through adoptive transfer back into the same patient, treat various cancers. Our previous work in engineering signaling control circuits in T cells demonstrates that T cells are amenable to high level genetic reprogramming. Together, these results illustrate the potential of using T cells as smart therapy. Here we propose to develop the next generation of T cell-based cancer therapy to directly address cancer heterogeneity. We will leverage our expertise in synthetic gene circuits and T cell engineering to develop novel gene networks in T cells that control when, where, and which cancer-specific receptors are being expressed, thus reprogramming the spatial and temporal activity of cancer killing T cells. Our first class of synthetic gene networks will address the inter-patient heterogeneity by controlling the activity of engineered T cell in vivo based on how individual patient respond to the adoptive therapy, relying on the administration of small molecules that serves as the trigger of the network. Our second class of gene networks will combat intra-patient heterogeneity by directing T cells to tumors through receptors targeted to a specific cancer antigen, and then non-selectively killing the surrounding tumor cells for a defined duration of time. This allows the elimination of many cancerous cell types simultaneously without causing systemic toxicity. Success from this proposal will result in paradigm-shifting therapies with unprecedented level of flexibility, precision, and personalization. The resulting engineered T cells will be the most sophisticated therapeutic agents ever developed. Furthermore, the genetic circuits and design principle developed here will serve as a general platform that can be combined with any tumor-specific receptors and complement existing adoptive T cell therapy, thus this work will have immediate and broad impact on many cancers. By bringing two emerging fields of science-cell-based immunotherapy and synthetic biology- to cancer research, results from this proposal will fundamentally change cancer treatment.