Replication Competent Adenovirus-mediated Cytotoxic and Interleukin-12 Gene Therapy in Prostate Cancer: 36 Month Follow-Up Data from a Phase I Clinical Trial

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Conference Proceeding

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Cancer Clin Trials


Background: Men with locally recurrent prostate cancer, after definitive radiotherapy, have few therapeutic options that have a high likelihood of eradicating the tumor with a reasonable degree of safety. Oncolytic adenovirus-mediated cytotoxic gene therapy is an investigational cancer therapy that is currently being evaluated in clinical trials. Delivery of the suicide gene to the tumor is usually accomplished by direct intratumoral or systemic injection of a viral vector containing the suicide gene. Two suicide genes that have been evaluated in preclinical models and in the clinic are the E. Coli coli cytosine deaminase (CD) and herpes simplex virus thymidine kinase (HSV-1 TK), which confer sensitivity to 5-fluorocytosine (5-FC) and ganciclovir (GCV), respectively. The pro-drugs are converted into active drugs that block DNA synthesis. In the past we have evaluated the toxicity and efficacy of oncolytic adenovirus-mediated cytotoxic gene therapy in five different clinical trials in prostate cancer, including a prospective randomized phase 2 study. In this Phase I trial we evaluated the safety of oncolytic adenovirus-mediated suicide and interleukin-12 (IL12) gene therapy in recurrent prostate cancer patients. Objectives: Phase I dose-escalation trial to evaluate the maximum tolerated dose (MTD) of replication competent adenovirus type 5 gene therapy with interleukin-12 delivered using ultrasound guided intraprostatic injection. Methods: Replication-competent adenovirus (Ad5-yCD/mutTKSR39- rep-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 oral prodrugs, 5-fluorocytosine (5-FC) and Valganciclovir (vGCV) therapy for 7 days. The study endpoint was toxicity through day 30. Experimental endpoints included measurements of serum IL12, interferon gamma (IFN-gamma), and CXCL10 to assess immune system activation. Peripheral blood mononuclear cells (PBMC) and proliferation markers were analyzed by flow cytometry. Results: 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, IFN-gamma, and CXCL10 levels were detected in 57%, 93%, and 79% of subjects, respectively. Serum cytokines demonstrated viral dose dependency, especially apparent in cohorts 4 and 5. Analysis of immune cell populations indicated activation after Ad5-yCD/mutTKSR39rep-hIL-12 administration in cohort 5. There was no correlation between adenoviral dose and PSA doubling time (PSADT). Conclusions: Ultrasound guided intraprostatic injection of replication competent adenovirus type 5 containing wo suicides genes and interleukin- 12 is well tolerated up to a dose of 1 × 1012 viral particles. The study maximum tolerated dose (MTD) was not reached. Further studies will be done to evaluate efficacy of this therapeutic approach in patients with locally recurrent prostate cancer.





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