Pathotropic nanoparticles for cancer gene therapy Rexin-G™ IV: Three-year clinical experience

Abstract

Abstract. 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.

The ‘timely’ development of Rexin-G: First targeted injectable gene vector (Review)

“…3-5). By quantifying the amounts of Rexin-G that are needed to 'meet and match' the progression and spread of a given type of end-stage cancer, a 'Calculus of Parity' was developed (17,18) which adds a predictive pharmacological component in terms of calculating the approximate cumulative doses of vector needed for a given patient's tumor-burden. In addition to defining the biologic thresholds and parities needed for Rexin-G monotherapy to achieve a significant level of tumor control, it is anticipated that additional mathematical formulations will be forthcoming to further define the optimal induction and maintenance protocols, as well as optimal dosing for Rexin-G when used in combination and/or adjuvant settings.…”

“…Following extensive preclinical studies of gene delivery, safety, efficacy and biodistribution, Rexin-G was first deployed against Stage IV pancreatic cancer in the Philippines under approved Compassionate Use protocols in a remarkable example of international cooperation. The innovative protocols utilized intrapatient dose escalations of intravenous Rexin-G (based on preclinical studies), which carefully monitored safety parameters before proceeding to the next higher doses (16)(17)(18). The promising results of these initial Compassionate Use studies, which soon thereafter extended to the United States, were sufficient in terms of documented safety and efficacy (as well as the lack of available treatments for this chemotherapy-resistant cancer) for the U.S. FDA to grant Orphan Drug Status in 2003.…”

“…The delivery of cytocidal genetic constructs that effectively destroy the target tumor cells and/or their associated blood supply eliminates the major problems associated with insertional mutagenesis and engraftment of genetically altered cells, which has plagued gene therapy applications in the past. The singular limitation of retroviral vectors that previously stymied the clinical development of these otherwise ideal gene delivery vehicles was the inability to effectively target these stealth nanoparticles under physiological conditions (22)(23)(24), a precondition that remained daunting until the advent of pathotropic targeting (11)(12)(13)(14)(15)(16)(17)(18)(19) (also see section 4).…”

“…The review assumes a posture of the medical avant-garde, but does not assume that the reader is either a molecular, genetic, or biotechnological cognoscente. The subject matter addressed herein is necessarily focused on very recent developments in the field, while pertinent background material on applied nanotechnology (2,3), gene delivery vehicles (4)(5)(6), cell cycle control (7,8), virotherapy (9,10) and tumor targeting technologies (11)(12)(13)(14)(15), as well as early clinical trials of Rexin-G (16)(17)(18) and associated histopathology (19) are available in the existing literature. The text is divided into discrete subsections in which critical distinctions are made and considered opinions are presented, in a strategic flow of contextual information that travels from the theoretical to the clinical to the analytical and beyond, to the evolving praxis of modern medicine.…”

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

“…By targeting and thus aborting this critical regulatory component of the cell's universal replication machinery, Rexin-G is invariably lethal to cancer cells derived from all three germ layers, including their associated proliferative vasculature, which empowers Rexin-G with potent anti-angiogenic properties (3,4), as well as broad spectrum tumoricidal activity (5)(6)(7). Each therapeutic nanoparticle incorporates a highly efficient and exquisitely specific targeting function to seek out and accumulate in cancerous tissues, using the abnormal or 'pathological' properties of the disease itself, specifically, the newly exposed collagenous proteins associated with cancer growth, metastasis, and tumor-associated blood vessel formation (8).…”