Ad3-hTERT-E1A, a Fully Serotype 3 Oncolytic Adenovirus, in Patients With Chemotherapy Refractory Cancer

Abstract

Twenty-five patients with chemotherapy refractory cancer were treated with a fully serotype 3-based oncolytic adenovirus Ad3-hTERT-E1A. In mice, Ad3 induced higher amounts of cytokines but less liver damage than Ad5 or Ad5/3. In humans, the only grade 3 adverse reactions were self-limiting cytopenias and generally the safety profile resembled Ad5-based oncolytic viruses. Patients that had been previously treated with Ad5 viruses presented longer lasting lymphocytopenia but no median increase in Ad3-specific T-cells in blood, suggesting immunological activity against antigens other than Ad3 hexon. Frequent alterations in antitumor T-cells in blood were seen regardless of previous virus exposure. Neutralizing antibodies against Ad3 increased in all patients, whereas Ad5 neutralizing antibodies remained stable. Treatment with Ad3-hTERT-E1A resulted in re-emergence of Ad5 viruses from previous treatments into blood and vice versa. Signs of possible efficacy were seen in 11/15 (73%) patients evaluable for tumor markers, four of which were treated only intravenously. Particularly promising results were seen in breast cancer patients and especially those receiving concomitant trastuzumab. Taken together, Ad3-hTERT-E1A seems safe for further clinical testing or development of armed versions. It offers an immunologically attractive alternative, with possible pharmacodynamic differences and a different receptor compared to Ad5.

Intravenously usable fully serotype 3 oncolytic adenovirus coding for CD40L as an enabler of dendritic cell therapy

“…Serotype 3 was selected over the more common serotype 5 because human data from ATAP ( Fig 1A) and based on a previous publication indicating that the Ad3 capsid allows effective intravenous delivery. 15 To make virus replication tumor selective, the endogenous promoter of E1A was replaced with the promoter of the catalytic subunit of human telomerase (hTERT) which is active in most human tumors. [46][47][48] To allow high level expression of CD40L in both tumor cells and the TME where DCs are located, a CMV promoter was placed in the E3 region to drive the CD40L transgene (2A).…”

“…15 Tumor biopsies on day 6 after treatment showed the presence of virus genomes (Fig. 1A), indicating that intravenous administration of Ad3 leads to transduction of distant tumors.…”

“…A breast cancer patient participating in the Advanced Therapy Access Program (ATAP) 15 was safely treated with Ad3-hTERT-E1A (CGTG-201) at 4 £ 10 12 VP intravenously. Tumor biopsies were collected 6 d later and presence of virus was detected with qPCR.…”

“…A Day 0 biopsy was not available but is has been shown that ATAP patients are negative for this virus at baseline. 15 DC activation in patients following treatment with CD40L encoding oncolytic adenovirus Cancer patients were treated with oncolytic adenoviruses either coding for CD40L or GMCSF in ATAP. Post-treatment tumor biopsies from these patients showed that hCD40L coding adenoviruses induced upregulation of genes associated with DC maturation and differentiation (Fig.…”

“…14 Oncolytic adenovirus Ad3-hTERT-E1A appears to be safe and effective in the laboratory as well as in cancer patients. 15 CD40L is a transmembrane type II protein expressed on CD4 C T cells, whereas its receptor is predominantly expressed on antigen-presenting cells (APCs). 16,17 DCs, which are professional APCs, express CD40 and get activated upon interaction with CD40L, which leads to priming of T cells followed by cytokine production and an immune response.…”