Oncolytic Adenovirus ICOVIR-7 in Patients with Advanced and Refractory Solid Tumors

Abstract

Purpose: Twenty-one patients with cancer were treated with a single round of oncolytic adenovirus ICOVIR-7. Experimental Design: ICOVIR-7 features an RGD-4C modification of the fiber HI-loop of serotype 5 adenovirus for enhanced entry into tumor cells. Tumor selectivity is mediated by an insulator, a modified E2F promoter, and a Rb-binding site deletion of E1A, whereas replication is optimized with E2F binding hairpins and a Kozak sequence. ICOVIR-7 doses ranged from 2 × 1010 to 1 × 1012 viral particles. All patients had advanced and metastatic solid tumors refractory to standard therapies. Results: ICOVIR-7 treatment was well tolerated with mild to moderate fever, fatigue, elevated liver transaminases, chills, and hyponatremia. One patient had grade 3 anemia but no other serious side effects were seen. At baseline, 9 of 21 of patients had neutralizing antibody titers against the ICOVIR-7 capsid. Treatment resulted in neutralizing antibody titer induction within 4 weeks in 16 of 18 patients. No elevations of serum proinflammatory cytokine levels were detected. Viral genomes were detected in the circulation in 18 of 21 of patients after injection and 7 of 15 of the samples were positive 2 to 4 weeks later suggesting viral replication. Conclusions: Overall, objective evidence of antitumor activity was seen in 9 of 17 evaluable patients. In radiological analyses, 5 of 12 evaluable patients had stabilization or reduction in tumor size. These consisted of one partial response, two minor responses and two cases of stable disease, all occurring in patients who had progressive disease before treatment. In summary, ICOVIR-7 treatment is apparently safe, resulting in anticancer activity, and is therefore promising for further clinical testing. Clin Cancer Res; 16(11); 3035–43. ©2010 AACR.

Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy

“…This increases the antitumor potential and efficacy of nanocarriers, since they decrease the nutrients and oxygen delivery to the tumors, and release the low molecular anticancer drugs in the vicinity of the tumor vasculature [49,85]. This promising strategy is under preclinical development, with a few clinical examples in phase I [87][88][89]. An additional drawback, that contributes to the current clinical failure of active targeting nanocarriers, comprises the increased immunogenicity and plasma protein adsorption when targeting moieties are included in the nanocarriers, decreasing their bloodstream circulation time and their ability to passively target the tumors [85].…”

Immune Response Is an Important Aspect of the Antitumor Effect Produced by a CD40L-Encoding Oncolytic Adenovirus

“…Oncolytic adenoviruses have shown safety in clinical trials and some efficacy has also been seen (1)(2)(3)(4). Importantly, it has been discovered that immunologic factors are critical with regard to efficacy of oncolytic viruses (5) and some investigators consider them a sophisticated form of immunotherapy (6).…”

Use and Safety of Intratumoral Application of European Mistletoe (Viscum album L) Preparations in Oncology

“…1,2 Anticancer agents that have been applied via IT injection include chemotherapy agents (eg, vincristine), oncolytic viruses (eg, ONYX-015), immunomodulators (eg, agonistic CD40 monoclonal antibodies), and autologous immune cells (eg, dendritic cells). [2][3][4][5][6][7][8][9] Potential advantages of IT delivery of anticancer drugs include better anticancer effectiveness through achievement of high concentrations of anticancer agents within the tumor microenvironment and reduced systemic adverse drug reactions (ADRs) and drug resistance. 5,[10][11][12] In general, single-agent efficacy has been less than satisfying to date; however, promising results have been achieved using IT-administered targeted therapies, combined with conventional chemotherapy or radiation.…”