Targeting metastatic cancer from the inside: a new generation of targeted gene delivery vectors enables personalized cancer vaccination in situ.

The advent of pathotropic (disease-seeking) targeting technologies, combined with advanced gene delivery vectors, provides a unique opportunity for the systemic delivery of immunomodulatory cytokine genes to remote sites of cancer metastasis. When injected intravenously, such pathotropic nanoparticles seek out and accumulate selectively at sites of tumor invasion and neo-angiogenesis, resulting in enhanced gene delivery, and thus cytokine production, within the tumor nodules. Used in conjunction with a primary tumoricidal agent (e.g., Rexin-G) that exposes tumor neoantigens, the tumor-targeted immunotherapy vector is intended to promote the recruitment and activation of host immune cells into the metastastic site(s), thereby initiating cancer immunization in situ. In this study, we examine the feasibility of cytokine gene delivery to cancerous lesions in vivo using intravenously administered pathotropically targeted nanoparticles bearing the gene encoding granulocyte/macrophage colony-stimulating factor (GM-CSF; i.e., Reximmune-C). In vitro, transduction of target cancer cells with Reximmune-C resulted in the quantitative production of bioactive and immunoreactive GM-CSF protein. In tumor-bearing nude mice, intravenous infusions of Reximmune-C-induced GM-CSF production by transduced cancer cells and paracrine secretion of the cytokine within the tumor nodules, which promoted the recruitment of host mononuclear cells, including CD40+ B cells and CD86+ dendritic cells, into the tumors. With the first proofs of principle established in preclinical studies, we generated an optimized vector configuration for use in advanced clinical trial designs, and extended the feasibility studies to the clinic. Targeted delivery and localized expression of the GM-CSF transgene was confirmed in a patient with metastatic cancer, as was the recruitment of significant tumor-infiltrating lymphocytes (TILs). Taken together, these studies provide the first demonstrations of cytokine gene delivery to cancerous lesions following intravenous administration and extend the applications of cancer immunization in vivo.

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

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.

Pathotropic nanoparticles for cancer gene therapy Rexin-G IV: three-year clinical experience.

Metastatic cancer is a life-threatening illness with a predictably fatal outcome, thereby representing a major unmet medical need. In 2003, Rexin-G became the world's first targeted injectable vector approved for clinical trials in the treatment of intractable metastatic disease. Uniquely suited, by design, to function within the context of the human circulatory system, Rexin-G is a pathotropic (disease-seeking) gene delivery system bearing a designer killer gene; in essence, a targeted nanoparticle that seeks out and selectively accumulates in metastatic sites upon intravenous infusion. The targeted delivery of the cytocidal gene to primary tumors and metastatic foci, in effective local concentrations, compels both cancer cells and tumor-associated neovasculature to self-destruct, without causing untoward collateral damage to non-target organs. In this study: i) we report the results of three distinctive clinical studies which demonstrate the initial proofs of concept, safety, and efficacy of Rexin-G when used as a single agent for advanced or metastatic cancer, ii) we introduce the quantitative foundations of an innovative personalized treatment regimen, designated the 'Calculus of Parity', based on a patient's calculated tumor burden, iii) we propose a refinement of surrogate end-points commonly used for defining success in cancer therapy, and iv) we map out a strategic plan for the accelerated approval of Rexin-G based on the oncologic Threshold of Credibility paradigm being developed by the Food and Drug Administration.

First clinical experience using a 'pathotropic' injectable retroviral vector (Rexin-G) as intervention for stage IV pancreatic cancer.

Metastatic or non-resectable (stage IV) pancreatic cancer has a rapidly fatal outcome (median survival: 3-6 months), thus making gene therapy a viable therapeutic option. The objectives of the clinical studies are to evaluate the safety/toxicity and potential anti-tumor response/efficacy of intravenous (i.v.) infusions of a 'pathotropic' retroviral vector bearing a cytocidal gene construct (Rexin-G) as a gene transfer intervention for stage IV pancreatic cancer. An intra-patient dose escalation regimen was used wherein increasing doses of Rexin-G were given i.v. daily for 8-10 days. Completion of this regimen was followed by a one-week evaluation period for toxicity, after which, the maximum tolerated dose of Rexin-G was administered for another 8-10 days. In a second protocol, i.v. Rexin-G was administered frontline for 6 days followed by 8 doses of weekly gemcitabine. The NIH Common Toxicity Criteria Vs.2 was used to assess toxicity, and the NCI-RECIST criteria and tumor volume measurements were used to evaluate potential anti-tumor responses. We report the results of the first 3 patients that participated in the studies. Rexin-G arrested tumor growth in 3 of 3 patients without experiencing dose-limiting toxicity. No bone marrow suppression, significant alterations in liver and kidney function, nausea and vomiting, mucositis or hair loss were observed. Two patients are alive with stable disease approximately 5 and 14 months from diagnosis, and 1 patient is alive with progressive disease 20 months from diagnosis. The encouraging results of this first clinical experience will guide the design and planning of phase I/II clinical trials to establish the safety and efficacy of Rexin-G as the first targeted injectable gene therapy vector for stage IV pancreatic cancer.

Pathotropic targeting advances clinical oncology: tumor-targeted localization of therapeutic gene delivery.

The advent of pathotropic (disease-seeking) targeting has transported genetic medicine across the threshold of history with the progressive clinical validation of Rexin-G, a tumor-targeted nanosized anti-cancer agent. Achieving noteworthy single-agent efficacy and survival benefits in otherwise intractable cancers, the molecular biotechnology platform has stimulated intense interest in the underlying mechanisms-of-action. This report exhibits the effective localization of Rexin-G nanoparticles within a metastatic liver lesion, as observed upon its surgical excision.