Gordon Erlinda M, Chan Maria Teresa, Geraldino Nelson, Lopez Francisco F, Cornelio Gerardo H, Lorenzo Conrado C, Levy John P, Reed Rebecca A, Liu Liqiong, Hall Frederick L
Asian Hospiatal and Medical Center, Manila, Philippines.
Int J Oncol. 2007 Jun;30(6):1297-307.
The pathotropic targeting of therapeutic nanoparticles to cancerous lesions is an innovative concept that has recently been reduced to practice in clinical trials for the treatment of metastatic cancer. Previously, we reported that intravenous infusions of Rexin-G, a pathotropic nanoparticle (or vector) bearing a cyto-ablative construct, induced tumor regression, reduced tumor burden, and improved survival, while enhancing the overall quality-of-life of patients with otherwise intractable chemotherapy-resistant cancers. In this report, we describe the major histopathological and radiologic features that are characteristic of solid tumors under the destructive influences of Rexin-G administered as a single therapeutic agent. To further promote tumor eradication and enhance cancer survival, we explored the potential of an auxiliary gene transfer strategy, specifically intended to induce a localized cancer auto-immunization in addition to assisting in acute tumor destruction. This immunization strategy uses Rexin-G in combination with Reximmune-C, a tumor targeted expression vector bearing a granulocyte macrophage-colony stimulating factor (GM-CSF) gene. Intravenous infusions of Rexin-G were given first to induce apoptosis and necrosis in the metastatic tumor nodules, thus exposing tumor neo-antigens, followed by Reximmune-C infusions, intended to recruit immune cells discretely into the same compartments (or lesions). The intent of this two-step approach is to bring a complement of cells involved in humoral and cell-mediated immunity in close proximity to the immunizing tumor antigens in a concerted effort to assist in tumor eradication and to promote a cancer vaccination in situ. Herein, we also describe the distinctive histopathologic and immunocytochemical features of tumors in terminal cancer patients who received Rexin-G infusions in combination with Reximmune-C. In addition to documenting the first histological indications of clinical efficacy achieved by this novel personalized approach to cancer vaccination, we discuss new methods and strategies for advancing its therapeutic utility. Taken together with the clinical data, these histological studies serve as valuable landmarks for medical oncology, and as definitive benchmarks for the emerging field of cancer gene therapy.
治疗性纳米颗粒对癌性病变的靶向作用是一个创新概念，最近已在转移性癌症治疗的临床试验中付诸实践。此前，我们报道静脉输注Rexin-G，一种携带细胞消融构建体的靶向纳米颗粒（或载体），可诱导肿瘤消退、减轻肿瘤负荷并提高生存率，同时改善对常规化疗耐药癌症患者的整体生活质量。在本报告中，我们描述了作为单一治疗剂施用的Rexin-G的破坏性影响下实体瘤的主要组织病理学和放射学特征。为了进一步促进肿瘤根除并提高癌症患者生存率，我们探索了辅助基因转移策略的潜力，该策略除了协助急性肿瘤破坏外，还专门用于诱导局部癌症自身免疫。这种免疫策略将Rexin-G与Reximmune-C联合使用，Reximmune-C是一种携带粒细胞巨噬细胞集落刺激因子（GM-CSF）基因的肿瘤靶向表达载体。首先静脉输注Rexin-G以诱导转移性肿瘤结节中的细胞凋亡和坏死，从而暴露肿瘤新抗原，随后输注Reximmune-C，旨在将免疫细胞离散地募集到相同的区域（或病变部位）。这种两步法的目的是使参与体液免疫和细胞介导免疫的细胞补充物与免疫肿瘤抗原紧密接近，共同协助肿瘤根除并促进原位癌症疫苗接种。在此，我们还描述了接受Rexin-G与Reximmune-C联合输注的晚期癌症患者肿瘤的独特组织病理学和免疫细胞化学特征。除了记录这种新型个性化癌症疫苗接种方法取得的临床疗效的首个组织学迹象外，我们还讨论了提高其治疗效用的新方法和策略。这些组织学研究与临床数据一起，是医学肿瘤学的宝贵标志，也是癌症基因治疗新兴领域的明确基准。
