Characterisation of a novel phage-guided gene delivery vector and investigation of its gene therapy efficacy against metastatic cancer.

大多数癌症患者死于转移，这些转移是在癌细胞离开初始部位或原发肿瘤以扩散并在其他组织中形成继发肿瘤或转移后建立的。传统疗法(手术、放疗和化疗)治疗转移的失败与位于不同组织的大量转移有关，需要系统治疗才能达到所有这些转移。传统的全身化疗药物已被使用，但往往无效，主要是因为它们没有选择性，导致它们在健康组织中积聚，这伴随着严重的副作用，限制了患者注射的化疗剂量。基因治疗，或利用基因治疗，是一种很有前途的治疗转移性癌症的方法。基因治疗需要载体(载体或递送系统)来携带治疗性基因并在肿瘤部位实现递送。人类病毒主要被用来设计基因治疗的载体，因为它们可以进入人类细胞，并作为其自然感染过程的一部分传递治疗性基因。癌症的基因治疗已经尝试了26年以上。然而，与化疗一样，基因治疗也面临着一个重大挑战，在全身给药后也一直无效，限制了其对转移瘤的有效性，因为只有通过全身基因治疗才能对转移癌产生真正的临床益处。这些挑战与基因治疗的载体有关，因为这些载体积累在各种健康组织中，并被针对这些病毒载体的身体免疫反应中和。我们以前的工作表明，无害和非致病的噬菌体，即只感染细菌的病毒，如果被设计成在衣壳上显示配体，就可以将基因输送到人类细胞。这些配体允许噬菌体与人类细胞上的受体结合，导致它们进入细胞并表达治疗基因。如果靶受体在癌症中是特异的，那么在全身给药后，噬菌体载体就成为靶向，以向癌症输送治疗基因，同时保留健康组织。我们的第一代噬菌体载体在静脉给药后，在癌症的临床前模型中显示了安全性和抗肿瘤效果。在过去的10年里，我们一直在改进这些载体，并产生能够克服它们限制的系统，因为噬菌体已经进化到只感染细菌，而没有开发出在人类细胞中表达基因的策略。事实上，基因治疗的有效性取决于载体在肿瘤治疗水平上表达基因的能力。重要的是，最近我们的努力已经产生了一种噬菌体载体，它可能在转移性癌症的系统基因治疗方面取得突破。进行这项工作很重要，因为该载体显示了克服癌症基因治疗所面临的主要限制的能力，并可能实现基因治疗拯救致命转移癌症患者生命的承诺。

The majority of cancer patients die because of metastases which are established after cancer cells leave their initial site or primary tumour in order to spread and form secondary tumours or metastases in other tissues. Failure of conventional therapies (surgery, radiotherapy and chemotherapy) to treat metastases is associated with the high number of metastases located in various tissues, requiring systemic treatment to reach all these metastases. Conventional systemic chemotherapeutic agents have been used but often ineffective, mostly because they are not selective, resulting in their accumulation in healthy tissues, which comes with sever side effects limiting the chemotherapeutic dose to be injected to patients. Gene therapy, or therapy using genes, is a promising treatment approach against metastatic cancer. Gene therapy requires a vector (vehicle or delivery system) to carry the therapeutic gene and achieve its delivery at the tumour site. Human viruses have mostly been used to design vectors of gene therapy because they can enter human cells and deliver therapeutic genes as part of their natural infection process. Gene therapy for cancer has been attempted for more than 26 years. However, like chemotherapy, gene therapy has faced a major challenge that has also been inefficacy after systemic administration, limiting its effectiveness against metastases since real clinical benefit against metastatic cancer can only happen with systemic gene therapy. These challenges are associated with vectors of gene therapy, since the vectors accumulate in various healthy tissues and get neutralized by the body immune response against these viral vectors. Our previous work shows that the harmless and non-pathogenic bacteriophage or phage, viruses that infect bacteria only, can deliver genes to human cells if they are engineered to display ligands on their capsid. These ligands allow the bacteriophage to bind to receptors on human cells resulting in their entry into the cells and expression of the therapeutic genes. If the target receptor is specific in cancer, then the phage vector becomes targeted after systemic administration to deliver therapeutic genes to cancer while sparing the healthy tissues. Our first generation of these phage vectors showed safety and anti-tumour efficacy in preclinical models of cancer after intravenous administration. We have spent the last 10 years to improve these vectors and generate systems that can overcome their limitations since bacteriophages have evolved to infect bacteria only with no developed strategies to express genes in human cells. Indeed efficacy of gene therapy depends on the ability of vectors to express genes at therapeutic levels in tumours. Importantly, very recently our efforts have yielded a bacteriophage vector that could make a breakthrough in systemic gene therapy of metastatic cancer. It is important to undertake this work because the vector shows ability to overcome major limitations that cancer gene therapy has faced and could bring to fruition the promise of gene therapy to save the lives of patients with deadly metastatic cancers.