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，这是在癌细胞离开其初始部位或原发肿瘤以扩散并在其他组织中形成继发性肿瘤或转移后建立的。常规治疗方法（手术、放疗和化疗）治疗转移性肿瘤的失败与大量转移灶位于各种组织有关，需要全身治疗才能到达所有这些转移灶。传统的全身化疗药物已经被使用，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累，这伴随着严重的副作用，限制了向患者注射的化疗剂量。基因治疗，或使用基因治疗，是一种很有希望的治疗转移性癌症的方法。基因治疗需要载体（载体或传递系统）携带治疗基因并实现其在肿瘤部位的传递。人类病毒主要用于设计基因治疗载体，因为它们可以进入人类细胞并将治疗基因作为其自然感染过程的一部分。基因治疗癌症的尝试已经超过了26年。然而，与化疗一样，基因治疗也面临着一个主要挑战，即全身给药后无效，限制了其对转移性癌症的有效性，因为对转移性癌症的真正临床获益只能通过全身基因治疗来实现。这些挑战与基因治疗载体有关，因为载体在各种健康组织中积累，并被针对这些病毒载体的身体免疫反应中和。我们之前的工作表明，无害和非致病性噬菌体或噬菌体，仅感染细菌的病毒，如果它们被改造成在其衣壳上显示配体，就可以将基因传递给人类细胞。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。如果目标受体在癌症中是特异性的，那么噬菌体载体在系统给药后成为靶向，将治疗基因传递给癌症，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的临床前癌症模型中显示出安全性和抗肿瘤功效。我们花了过去10年的时间来改进这些载体，并产生能够克服其局限性的系统，因为噬菌体已经进化到只能感染细菌，而没有开发出在人类细胞中表达基因的策略。事实上，基因治疗的效果取决于载体在肿瘤中表达治疗水平基因的能力。重要的是，最近我们的努力已经产生了一种噬菌体载体，可能在转移性癌症的系统性基因治疗方面取得突破。开展这项工作很重要，因为载体显示出克服癌症基因治疗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性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.