Adenovirus/Chemotherapy Combination Well-Tolerated, Surprising OS Benefit Observed in mPC

A novel adenovirus gene therapy, Ad5-yCD/mutTKSR39rep-hIL12, in combination with chemotherapy, was well tolerated in patients with metastatic pancreatic cancer (mPC) with promising overall survival (OS) benefits.

Findings from a single site, nonrandomized, dose-escalation phase 1 trial (NCT03281382) assessing the combination were presented at the American Society for Gene and Cell Therapy 25th Annual Meeting, May 16-19, 2022, in Washington DC, by Syham Nyati, PhD, department of radiation oncology, Henry Ford Health System.

"We think for metastatic cancer patients that with just a single dose of virus injection and just 7 days of fluorocytosine injection, we could actually make patients live longer. This was not expected... The patient number here is very small so we want to do a phase 2 trial,” Nyati said during his presentation.

Nyati and colleagues at Henry Ford Health System evaluated the adenovirus combination for safety as measured by dose limiting toxicities (DLTs) at 21 days after treatment and to determine the maximum tolerated dose. A secondary endpoint was grade 3 Common Terminology Criteria for Adverse Events (CTCAE) and the trial also assessed exploratory endpoints such as viral distribution, immunological cytokines and clinical outcomes, although OS was not an endpoint.

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Ad5-yCD/mutTKSR39rep-hIL12 is a replication competent adenovirus that consists of the suicide genes HSV-TK and yCD and an IL-12 expression cassette. Men and women with mPC were enrolled between October 2017 and May 2019. Participants received a single intratumoral injection of the IL-12 adenovirus, which was guided by endoscopic ultrasound.

Patients were dosed in 3 cohorts of 1X10¹¹ virus particles (vp; n = 3), 3X10¹¹ vp (n = 3) or 1X10¹² vp (n = 6) and 150 mg/kg/day oral 5-fluorocytosine was administered to patients 2 days after the injection for 7 days. The treating physician decided on a course of chemotherapy 14 days after the prodrug course.

Investigators monitored AEs such as toxicity, viral load, immunological cytokines, and immune cell activation up to day 21. Patients in the first 2 cohorts did not experience AEs but the first patient in the third cohort did experience an AE.

Investigators did not find a maximum tolerated dose in the study. Several patients exhibited viral load for up to 2 weeks post-injection and had increased serum cytokines such as IL12, IFNγ, and CXCL10, as well as increased CD4+ and CD8+ T-cells, but there were no significant differences between viral loads here.

Nyati and colleages found that participants dosed in the third, highest-dose cohort experienced a clinically meaningful OS benefit of 18.4 months compared with the 4.2-month OS benefit experienced by patients in the lower-dose cohorts (P = .01; Logrank test for trend, .009), although patient 9 in the third cohort passed away quickly. The OS analysis was conducted on March 9th, 2022 and 1 patient remains 35.7 months after treatment on maintenance chemotherapy.

“To our knowledge this is the first phase-1 trial which indicated median OS ~18 months for mPC patients,” Nyati and colleagues wrote.

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REFERENCE

Nyati S, Siddiqui F, Barton K, et al. Replication competent adenovirus-mediated cytotoxic and interleukin-12 gene therapy in stage iv pancreatic cancer: 36 month follow-up data from a phase I clinical trial. Presented at ASGCT 25th annual meeting, May 16-19, 2022; Washington DC.