Le morte du tumour: Histological features of tumor destruction in chemo-resistant cancers following intravenous infusions of pathotropic nanoparticles bearing therapeutic genes

Abstract

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.