Oncolytic virus TG6002 safety and activity after intrahepatic artery administration in patients with liverdominant metastatic colorectal cancer
Cancer Research Conference: American Association for Cancer Research Annual Meeting, ACCR
; 83(8 Supplement), 2023.
Artículo
en Inglés
| EMBASE | ID: covidwho-20242368
ABSTRACT
The TG6002.03 trial is a dose-escalation phase 1 clinical trial of TG6002 infusion via the hepatic artery in patients with liver-dominant colorectal cancer metastases. TG6002 is an engineered Copenhagen strain oncolytic Vaccinia virus, deleted of thymidine kinase and ribonucleotide reductase to enhance tumor selective viral replication and expressing FCU1, an enzyme converting the non-cytotoxic prodrug 5-fluorocytosine (5-FC) into the chemotherapeutic compound 5-fluorouracil (5-FU). In this trial, patients with advanced unresectable liver-dominant metastatic colorectal cancer who had failed previous oxaliplatin and irinotecan-based chemotherapy were treated with up to 2 cycles of TG6002 infusion 6 weeks apart via the hepatic artery on day 1 combined with oral 5-FC on days 5 to 14 (where day 1 = TG6002 infusion). TG6002 infusion was performed over 30 minutes via selective catheterization of the hepatic artery proper. 5-FC oral dosing was 50mg/kg x4 daily. Blood was sampled for TG6002 pharmacokinetics and 5-FC and 5-FU measurements. Sampling of liver metastases was performed at screening and on day 4 or day 8 for virus detection and 5-FC and 5-FU quantification. In total, 15 patients (median age 61 years, range 37-78) were treated in 1 UK centre and 2 centres in France and received a dose of TG6002 of 1 x 106 (n=3), 1 x 107 (n=3), 1 x 108 (n=3), or 1 x 109 pfu (n=6). Fourteen of the 15 patients received a single cycle of treatment, including one patient who did not received 5-FC, and one patient received two cycles. TG6002 was transiently detected in plasma following administration, suggesting a strong tissue selectivity for viral replication. In the highest dose cohort, a virus rebound was observed on day 8, concordant with replication time of the virus. In serum samples, 5-FU was present on day 8 in all patients with a high variability ranging from 0.8 to 1072 ng/mL and was measurable over several days after initiation of therapy. Seven of the 9 patients evaluable showed the biodistribution of the virus in liver lesions by PCR testing on day 4 or day 8. Translational blood samples showed evidence for T-cell activation and immune checkpoint receptor-ligand expression. At 1 x 109 pfu, there was evidence for T-cell proliferation and activation against tumour-associated antigens by ELISpot and for immunogenic cell death. In terms of safety, a total of 34 TG6002-related adverse events were reported, of which 32 were grade 1-2 and 2 were grade 3. The maximum tolerated dose was not reached, and a single dose-limiting toxicity was observed consisting of a myocardial infarction in a context of recent Covid-19 infection in a 78-year-old patient. These results indicate that TG6002 infused via the hepatic artery in combination with oral 5-FC was well tolerated, effectively localized and replicated in the tumor tissues, expressed its therapeutic payload and showed anti-tumoral immunological activity.
adult; advanced cancer; adverse drug reaction; aged; blood sampling; cancer chemotherapy; cancer combination chemotherapy; cancer patient; catheterization; cell proliferation; clinical trial; colorectal cancer; conference abstract; coronavirus disease 2019; drug combination; drug megadose; drug safety; drug therapy; enzyme linked immunospot assay; female; France; gene deletion; heart infarction; hepatic artery; human; human tissue; immunogenic cell death; liver injury; liver metastasis; major clinical study; male; maximum tolerated dose; metastasis; metastatic colorectal cancer; middle aged; multicenter study; pharmacokinetics; phase 1 clinical trial; proper hepatic artery; rebound; side effect; T lymphocyte; T lymphocyte activation; treatment failure; virus detection; virus replication; antiinfective agent; endogenous compound; flucytosine; fluorouracil; irinotecan; oncolytic vaccinia virus; oxaliplatin; prodrug; ribonucleotide reductase; thymidine kinase; tumor antigen
Texto completo:
Disponible
Colección:
Bases de datos de organismos internacionales
Base de datos:
EMBASE
Tipo de estudio:
Estudio de cohorte
/
Estudios diagnósticos
/
Estudio observacional
/
Estudio pronóstico
/
Ensayo controlado aleatorizado
Tópicos:
Vacunas
Idioma:
Inglés
Revista:
Cancer Research Conference: American Association for Cancer Research Annual Meeting, ACCR
Año:
2023
Tipo del documento:
Artículo
Similares
MEDLINE
...
LILACS
LIS