Shyam Nyati, Hans Stricker, Kenneth N. Barton, Pin Li, Mohamed Elshaikh,Haythem Ali, Stephen L. Brown, Clara Hwang, James Peabody, Svend O. Freytag, Benjamin Movsas, Farzan Siddiqui
Abstract
In a phase I dose escalation and safety study (NCT02555397), a replication-competent oncolytic adenovirus expressing yCD, TK and hIL-12 (Ad5-yCD/mutTKSR39rep-hIL-12) was administered in 15 subjects with localized recurrent prostate cancer (T1c-T2) at increasing doses (1 × 1010, to 1 × 1012 viral particles) followed by 7-day treatment of 5-fluorocytosine (5-FC) and valganciclovir (vGCV). The primary endpoint was toxicity through day 30 while the secondary and exploratory endpoints were quantitation of IL-12, IFNγ, CXCL10 and peripheral blood mononuclear cells (PBMC). The study maximum tolerated dose (MTD) was not reached indicating 1012 viral particles was safe. Total 115 adverse events were observed, most of which (92%) were grade 1/2 that did not require any treatment. Adenoviral DNA was detected only in two patients. Increase in IL-12, IFNγ, and CXCL10 was observed in 57%, 93%, and 79% patients, respectively. Serum cytokines demonstrated viral dose dependency, especially apparent in the highest-dose cohorts.
Introduction
Approximately 268,000 men are expected to be diagnosed with prostate cancer in USA in 2022 resulting in 34,500 deaths [1]. Nearly one-third of patients will elect radiation therapy (external beam and/or brachytherapy) as their primary treatment [2]. Radiotherapy provides exceptional long-term survival and disease control for men with localized, low-risk disease (Stage T1/T2, Gleason ≤ 6, PSA < 10 ng/mL) [2]. However, local recurrence rates are a challenge especially with more aggressive forms of the disease with higher Gleason scores and PSA (Stage ≥ T3, Gleason ≥ 7, PSA > 10 ng/mL). Fortunately, the rate of occult distal failure following definitive radiotherapy is < 10% at 10 years [3]. Hence, there is a substantial window of curative opportunity in men with localized recurrent disease. Men with locally recurrent prostate cancer after definitive radiotherapy have few therapeutic options that can potentially eliminate the tumor with acceptable safety. Other than expectant management and systemic therapy (i.e., androgen suppression therapy, AST), there are few local therapeutic options for locally recurrent prostate cancer such as salvage radical prostatectomy, salvage cryoablation, salvage brachytherapy, and salvage high-intensity focused ultrasound.
Materials and methods
Study design
The study was designed as a single site, prospective, non-randomized, phase I, classical 3+3 dose escalation trial of viral particles (vp). This trial was designed to enroll 15–30 men with locally recurrent prostate cancer after definitive radiotherapy under 5 cohorts with increasing doses. Each cohort of three patients with clinically localized recurrent prostate adenocarcinoma were intraprostatically injected with increasing doses (cohort-1 1x1010 vp, cohort-2 3x1010 vp, cohort-3 1x1011 vp, cohort-4 3x1011 vp, and cohort-5 1x1012 vp) of the Ad5-yCD/mutTKSR39rep-hIL-12 (Ad5-IL-12) adenovirus followed by one week (7 days) of 5-fluorocytosine and valganciclovir prodrug therapy. All subjects were treated in the Department of Radiation Oncology and the Department of Urology in the Henry Ford Cancer Institute, Henry Ford Health.
Results
Study design and patient baseline characteristics
All patients had recurrent prostate cancer following at least one cycle of radiation therapy. Patients received an intraprostatic injection of the Ad5-IL-12 adenovirus on day 1 at doses ranging from 1 × 1010 vp to 1 × 1012 vp (NCT02555397; Table 1 and Figs 1 and 2). Beginning on day 3 (day 1 being the day of Ad5-IL-12 adenoviral administration) patients started 5-FC and vGCV prodrugs for 1 week (7 days). A total of 15 patients in 5 cohorts were treated (Table 1). One patient (Patient #3) withdrew from the study on day 3. The median follow-up was 31 months (range 15–56 months). The median follow up was calculated from the date of adenoviral injection. The mean Gleason score was 7 while the most patients represented with T1c clinical stage. The mean PSA at the beginning of the gene therapy (Pre-Tx PSA) was 9.2 ng/ml (range 2.8–22.3 ng/ml). The adenovirus was deposited in all six sextants in all the patients except one patient in cohort 4 (Patient #12, 3 x 1011vp). The adenovirus dose distribution was skewed toward sextants with higher-grade (Gleason ≥7) cancer.
Discussion
The goal of this phase-1 clinical study was to estimate the maximum tolerated dose of oncolytic, cytotoxic Ad5-IL-12 gene therapy in men with recurrent prostate adenocarcinoma. Patients were administered increasing doses of Ad5-IL-12, ranging from 1 × 1010 to 1 × 1012 viral particles. Starting on day 3 after adenovirus injection, subjects received 7 days of 5-FC and vGCV prodrugs. Similar to previous studies conducted with equivalent oncolytic adenoviral vectors, majority (>90%) of the AEs in this study were mild to moderate (grade 1/2) that did not involve any medical intervention. No serious adverse events (SAEs) were encountered in the present study indicating that the maximum tolerated dose was not attained. This trial establishes that intra-prostatic injection of Ad5-IL-12 followed by 5-FC and vGCV prodrug therapy is safe.
Acknowledgments
The authors thank Yingshu Zhang for technical assistance and Dr. Kevin Bobbitt for running the samples for flow cytometry.
Citation: Nyati S, Stricker H, Barton KN, Li P, Elshaikh M, Ali H, et al. (2023) A phase I clinical trial of oncolytic adenovirus mediated suicide and interleukin-12 gene therapy in patients with recurrent localized prostate adenocarcinoma. PLoS ONE 18(9): e0291315. https://doi.org/10.1371/journal.pone.0291315
Editor: Sumit Kumar Hira, The University of Burdwan, INDIA
Received: April 14, 2023; Accepted: August 6, 2023; Published: September 15, 2023
Copyright: © 2023 Nyati et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting information files.
Funding: The work presented was partly supported by NIH-R21-CA252010 (co-PIs: MD Green and S Nyati) and NIH-R01-CA218596 (co-PIs: JR Ewing and S Brown). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: KNB and SOF hold a patent “Methods and Composition for Cancer Therapy Using a Novel Adenovirus” (#7,815,902 B2) for an adenovirus like the one used in this study, BM: Research support from Varian, ViewRay and Philips (no direct conflict), FS: Varian Medical Systems, Inc- Honorarium and travel reimbursement for lectures and talks, Varian Noona- Medical Advisory Board member- receive honorarium, CW: Clara Hwang: Stock holdings in Johnson and Johnson; research funding to institution from Merck, Bausch Health, Genentech, Bayer, and AstraZeneca, consultant fees from Tempus, Genzyme, and EMD Sorono, speaking fees from OncLive/MJH Life Sciences, travel fees from Merck, all outside the submitted work. SN: The work presented was partly supported by NIH-R21-CA252010 (co-PIs: MD Green and S Nyati). SB: The work presented was partly supported by NIH-R01-CA218596 (co-PIs: JR Ewing and S Brown). HA: participate in research activities with Novartis, Merck, Astra-Zeneca, Grail, and Pfizer. Receives consultation Honorarium from Astra-Zeneca, Seagen, Pfizer, OBI, cardinal health and Regeneron. HS, MA, JP, PL: no COI. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0291315#abstract0
