The accompanying abstract, courtesy of ASTRO:
>>Phase I dose-escalation study of tumor necrosis factor- gene transfer with radiation therapy for advanced solid tumors
A.K. Sharma 1, N. Hanna 2, J. Nemunaitis 3, M. Posner 4, A. Rosemurgy 5, S. Gupta 1, U. Hopkins 1, K. Chu 6, R. Weichselbaum 4 and S. Mani 1
[1] Radiation Oncology, Montefiore Medical Center, Bronx, NY, USA[2] Surgery, University of Kentucky Medical Center, Lexington, KY, USA[3] U.S.Oncology, U.S. Oncology, Dallas, TX, USA[4] Surgical Oncology, University of Chicago Medical Center, Chicago, IL, USA[5] Surgical Oncology, University of South Florida Medical Center, Tampa, FL, USA[6] Gen Vec, Gen Vec, Gaithersburg, MD, USA
Purpose: The anticancer activity of TNF-alpha is well documented. However, systemic toxicity has prevented wider clinical use. A gene therapy approach, using direct intra-tumoral injection in locally advanced cancer represents one way of maximizing local effect whilst minimizing systemic toxicity. TNFerade Biologic (TNFerade®) is a replication deficient adenovector containing the TNF gene, regulated by the radiation-sensitive promoter Egr-1. Based on a compelling in vitro and in vivo efficacy/safety profile of TNFerade®, given in conjunction with radiotherapy, we embarked on a phase I study to define tolerability and biologic effects of TNFerade® in patients with advanced solid malignancies.
Materials and Methods: Patients were required to harbor measurable tumors at sites amenable to repeated intra-tumoral injections. Two patients with chest wall masses have at the time of writing been enrolled in the protocol comprising twice-weekly injections on weeks 1 and 2 followed by weekly injections thereafter till 6 weeks. Radiation therapy commenced on week 2 and continued up to a maximum of 5 weeks. Tumor biopsies were obtained serially on week 1 and week 2 pre-injection, 24 hours and 4 days after injection to assess for TNF transgene expression in tumor or vascular endothelial cells.
Results: Maximal plasma concentrations after intra-tumoral injection of TNFerade® at a dose of 4 x109pu with radiation was ~ 7.3 pg/ml (day 5, week 2), which is far below the projected MTD (~14800pg/ml, based on literature), suggesting a large safety margin of the compound. One patient has completed a full course of radiation therapy to two lesions (one injected with TNFerade® and the other uninjected). Serial CAT scans revealed extensive necrosis in the injected lesion; however, the uninjected lesion shows minimal change from baseline at the end of radiotherapy. PET scan post-therapy confirmed differential necrosis in the injected lesion.
Conclusion: TNFerade® was well tolerated in the first two patients. Additional data on the biologic effects and safety of TNFerade® in current and future patients will be presented.<<
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Cheers, Tuck |
