Armed oncolytic viruses (OV) are a promising modality for the treatment of solid tumors. OVs exert their antitumoral activity through a selective replication in tumor cells and expression of therapeutic molecules. The use of OV in the clinic is limited by the intra-tumoral route. TG6002 is an OV of the Vaccinia Copenhagen strain, with two deletions in key viral genes to enhance replication selectivity in tumor cells, and expressing FCU1, an enzyme converting 5-FC into 5-FU. As part of a dose-escalation phase I trial, we showed that TG6002 was distributed and delivered its payload in tumor after IV administration in patients with advanced GI carcinomas.
15 patients (median age = 62 years), received TG6002 infusions on days 1, 8 and 15 at the dose of 3x108 pfu (n=3) ,1x109 pfu (n=10) or 3x109 pfu (n=2) combined with 5-FC (4 times 50 mg/kg/day) on days 5 to 7, 12 to 14, and 19 to 28. Blood was sampled 30 min, 3h and 24h after TG6002 infusion on day 1 and 15 for plasma TG6002 PK and on days 5, 7, 14 and 28 for serum 5-FC and 5-FU measurements. A biopsy was performed on day 5 along with blood sampling for virus level assessment by qPCR and plaque assay, and 5-FC and 5-FU quantification.
TG6002 was cleared from plasma within 3 hours in all patients. On day 5, as evidenced by qPCR or plaque assay, TG6002 was present in tumor in 1/3, 3/8 and 1/2 patients in the 3x108, 1x109 and 3x109 pfu cohorts, respectively. FCU1 activity was shown by measurement of 5-FU in serum and in biopsy specimens, suggesting that the virus was active in all patients albeit not always directly detectable. Levels of 5-FU in serum correlated with 5-FU concentration in tumors and highest levels were observed in patients with high level of TG6002 in tumor biopsies on day 5. This correlation suggests that FCU1 activity is localized in cancer cells and support TG6002 tumor selectivity. In terms of safety, TG6002 was well tolerated and no major toxicity limiting the dose-escalation was observed.
TG6002 localized to the tumor after IV administration in patients with advanced GI cancers and persisted selectively in tumors while expressing its transgene of interest. These data support the relevance of this route of administration in oncolytic virotherapy.
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K. Bendjama: Financial Interests, Personal, Project Lead, Transgene's employee: Transgene. P. Erbs: Financial Interests, Personal, Full or part-time Employment: Transgene. D. Carpentier: Financial Interests, Personal, Full or part-time Employment: Transgene. A. Sadoun: Financial Interests, Personal, Full or part-time Employment: Transgene. All other authors have declared no conflicts of interest.