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

描述（由申请人提供）：癌症是一种因患者体内和患者之间的高度细胞异质性而复杂化的致命疾病。目前的治疗药物并不是为了对抗这种异质性而设计的，这最终会导致更高的耐药性和复发的机会。因此，智能癌症治疗应该是特异性的，但能够解决癌症细胞显示的患者内部和患者之间的多样性。工程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新编程来检测疾病特异性信号，做出复杂的决定，执行适当的反应，并发展成记忆T细胞。这些特性即使不是不可能，也很难被设计成传统的治疗药物，比如小分子和抗体。最近的研究表明，患者的T细胞可以经过修饰，在体外表达一种癌症特异性受体，并通过过继移植回同一患者体内，治疗各种癌症。我们之前在T细胞中工程信号控制电路的研究表明，T细胞可以适应高水平的基因重编程。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细胞的癌症治疗来直接解决癌症的异质性。我们将利用我们在合成基因回路和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、何地以及哪些癌症特异性受体被表达，从而重新编程杀死癌症的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的活性来解决患者间的异质性

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.