Abstract CT196: A phase I clinical trial of oncolytic adenovirus mediated suicide and interleukin-12 gene therapy in patients with recurrent prostate cancer
Authors: Nyati Shyam , Stricker Hans , Barton Kenneth L. , Li Piln , Elshaikh Mohamed , Ali Haythem , Brown Stephen L. , Hwang Clara , Peabody James , Freytag Svend O. , Movsas Benjamin , Siddiqui Farzan 
Published: April 2023

Abstract
Introduction: Men with locally recurrent prostate cancer, after definitive radiotherapy, have few therapeutic options. Oncolytic adenovirus-mediated cytotoxic gene therapy is an investigational cancer therapy. Delivery of the suicide gene to the tumor is by direct intratumoral or systemic injection of a viral vector containing the suicide gene. Our approach incorporates yeast cytosine deaminase (yCD) and herpes simplex virus thymidine kinase (HSV-1 TK), to confer sensitivity to 5-fluorocytosine (5-FC) and Valganciclovir (vGCV), respectively. The pro-drugs are converted into active drugs that inhibit DNA damage repair. Here we report the safety of oncolytic adenovirus-mediated suicide gene therapy that incorporates an interleukin-12 (IL12) gene for treatment of recurrent prostate cancer.
Methods: In this phase I study, a replication-competent adenovirus (Ad5-yCD/mutTKSR39rep-hIL-12) expressing yCD/mutTKSR39 (yeast cytidine deaminase/mutant S39R HSV-1 thymidine kinase) and human IL-12 (IL12) was injected into tumors of 15 subjects with recurrent prostate cancer (T1c-T2) at escalating doses (1 × 1010, 3 × 1010, 1 × 1011, 3 × 1011, or 1 × 1012 viral particles). Subjects received 5-FC and vGCV for 7 days. The study endpoint was toxicity through day 30. Experimental endpoints included measurements of serum IL12, interferon gamma (IFNγ), and CXCL10 to assess immune system activation. Peripheral blood mononuclear cells (PBMC) and proliferation markers were analyzed by flow cytometry.
Results and Conclusions: Fifteen patients received Ad5-yCD/mutTKSR39rep-hIL-12 and oral 5-FC and vGCV. Approximately 92% of the 115 adverse events observed were grade 1/2 requiring no medical intervention. Ad5-yCD/mutTKSR39rep-hIL-12 DNA was detected in the blood of only two patients. Elevated serum IL12, IFNγ, and CXCL10 levels were detected in 57%, 93%, and 79% of subjects, respectively. Serum cytokines demonstrated viral dose dependency, especially apparent in the highest-dose cohorts. Analysis of immune cell populations indicated activation after Ad5-yCD/mutTKSR39rep-hIL-12 administration in cohort 5. The study did not detect a significant difference in the PSA doubling time (PSADT) between pre and post treatment by paired Wilcoxon rank test (p=0.17). There was no correlation between adenoviral dose and PSADT in each cohort separately or pooled (cohorts1-3 and cohorts 4-5). The study maximum tolerated dose (MTD) was not reached indicating 1012 viral particles was safe. This trial confirmed that replication-competent Ad5-IL-12 adenovirus (Ad5-yCD/mutTKSR39 rep-hIL-12) was well tolerated when administered locally to prostate tumors.
Citation Format: Shyam Nyati, Hans Stricker, Kenneth L. Barton, Piln Li, Mohamed Elshaikh, Haythem Ali, Stephen L. Brown, Clara Hwang, James Peabody, Svend O. Freytag, Benjamin Movsas, Farzan Siddiqui. A phase I clinical trial of oncolytic adenovirus mediated suicide and interleukin-12 gene therapy in patients with recurrent prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT196.