Phase 1 study of intravenous administration of the chimeric adenovirus enadenotucirev in patients undergoing primary tumor resection

Abstract

Background: Enadenotucirev (formerly ColoAd1) is a tumor-selective chimeric adenovirus with demonstrated preclinical activity. This phase 1 Mechanism of Action study assessed intravenous (IV) delivery of enadenotucirev in patients with resectable colorectal cancer (CRC), non-small-cell lung cancer (NSCLC), urothelial cell cancer (UCC), and renal cell cancer (RCC) with a comparator intratumoral (IT) dosed CRC patient cohort.

Methods: Seventeen patients scheduled for primary tumor resection were enrolled. IT injection of enadenotucirev (CRC only) was administered as a single dose (≤ 3 × 1011 viral particles [vp]) on day 1, followed by resection during days 8-15. IV infusion of enadenotucirev was administered by three separate doses (1 × 1012 vp) on days 1, 3, and 5, followed by resection during days 8-15 (CRC) or days 10-25 (NSCLC, UCC, and RCC). Enadenotucirev activity was measured using immunohistochemical staining of nuclear viral hexon and quantitative polymerase chain reaction for viral genomic DNA.

Results: Delivery of enadenotucirev was observed in most tumor samples following IV infusion, with little or no demonstrable activity in normal tissue. This virus delivery (by both IV and IT dosing) was accompanied by high local CD8+ cell infiltration in 80% of tested tumor samples, suggesting a potential enadenotucirev-driven immune response. Both methods of enadenotucirev delivery were well tolerated, with no treatment-associated serious adverse events.

Conclusions: This study provides key delivery and feasibility data to support the use of IV infusion of enadenotucirev, or therapeutic transgene-bearing derivatives of it, in clinical trials across a range of epithelial tumors, including the ongoing combination study of enadenotucirev with the checkpoint inhibitor nivolumab. It also provides insights into the potential immune-stimulating properties of enadenotucirev.

Trial registration: This MOA study was a phase 1, multicenter, non-randomized, open-label study to investigate the administration of enadenotucirev in a preoperative setting (ClinicalTrials.gov: NCT02053220).

Conflict of interest statement

Ethics approval and consent to participate

The study was approved by the institutional review board of each participating center, and was conducted according to the principles of the Declaration of Helsinki and the International Conference on Harmonisation (ICH) of Good Clinical Practice (GCP) guidelines. All patients provided written informed consent before study entry.

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1

Study design and patient disposition. a Two patients were excluded at screening because of inadequate renal function, and one because of bowel obstruction. b Cohorts C–E initiated after completion of cohort A and B comparison phase. c Enadenotucirev (EnAd) administration days also counted as assessment visits (i.e. cohort A: day 1; cohort B: days 1, 3, and 5)

Fig. 2

Nuclear staining of enadenotucirev in samples from selected CRC patients (IT injection versus IV infusion). 1. Image IT-204-B9-12 (top left), tumor section from a patient with CRC treated with enadenotucirev given by IT injection (cohort A): strong brown nuclear hexon staining of tumor cells is visible in the bottom part of the tissue section. 2. Image IT-204-B9-12 (top right), a different region of the same tumor section in 1: nuclear hexon staining of tumor cells is visible throughout this area of the tissue section. 3. Image IV-201-B10-9 (middle left), tumor section from a patient with CRC treated with enadenotucirev given by IV infusion (cohort B) but whose resection was delayed until day 52: nuclear hexon staining of tumor cells (but not stroma) is still visible in this tissue. 4. Image IV-101-B8-1 (middle right), non-tumor (presumed normal) section from a patient with CRC treated with enadenotucirev given by IV infusion (cohort B): little or no nuclear hexon staining is visible throughout the tissue section. 5. Image IV-302-B6-2 (bottom left), isotype staining control

Fig. 3

CD8 staining in samples from CRC patients (IT injection versus IV infusion). 1. Image IT-301-B3-7 (top panel), tumor section from a patient with CRC treated with enadenotucirev given by IT injection (cohort A): brown CD8 staining (× 10 magnification) can be clearly seen infiltrating the tumor cells. 2. Image IV-101-B4-7 (middle panel), tumor section from a patient with CRC treated with enadenotucirev given by IV infusion (cohort B): brown CD8 staining (× 10 magnification) infiltrating the tumor cells can be clearly seen. 3. Image IT-302-B3-7 (bottom panel), tumor section from a patient with CRC treated with enadenotucirev given by IT injection (cohort A): higher magnification (× 40) showing closer detail of CD8-stained cells, which appear pleomorphic, a hallmark of activated CD8+ T cells

Fig. 4

Enadenotucirev DNA detection in samples of epithelial tumors by qPCR (all cohorts). The exploratory qPCR analysis in patients with CRC and other tumor types provides supporting evidence demonstrating that enadenotucirev can be delivered to several different carcinoma types by IV infusion. Individual patient data are shown with corresponding identification in the key