Introduction
deaths, prostate tumor, prostate cancer, tumor
TUMOR, RECURRENT PROSTATE CANCER, PROSTATE TUMOR, TUMOR ANGIOGENESIS, PROSTATE CANCER
Approximately 268,000 men are expected to be diagnosed with prostate cancer in USA in 2022 resulting in 34,500 deaths [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. Although some have demonstrated encouraging 5-year disease-free survival rates in single institution studies, most are associated with some morbidity and there are no prospective randomized studies demonstrating their long-term effectiveness.Several oncolytic adenovirus-based cytotoxic gene therapy vectors are currently being evaluated in clinical trials. Delivery of a conditionally cytotoxic gene, termed a “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 cytosine deaminase (CD) from yeast or Phagocytes and dendritic cells secrete interleukin-12 (IL-12) in response to pathogens. Subsequently, IL-12 activates innate (natural killer, NK, and natural killer T lymphocytes, NKT) and adaptive (CD4+ Th and CD8+ Tc cells) immune system, causes IFN-γ secretion, enhances antigen presentation, and inhibits tumor angiogenesis.IL-12 has demonstrated significant anti-tumor activity in preclinical models including in prostate cancer [Consequently, we conducted an investigator-initiated phase I dose-escalation clinical trial to evaluate the maximum tolerated dose and safety of Ad5-IL-12 in men with recurrent localized prostate cancer. These men were administered Ad5-IL-12 directly into the prostate tumor at one of five escalating doses. Ad5-IL-12 viral replication, shedding and persistence was measured in patient blood (over time) by PCR. We also assessed the effect of the gene therapy on innate and adaptive immune system by quantitating peripheral blood mononuclear cells (PBMCs) before and after treatment with Ad5-IL-12 by flow cytometry. Additionally, IL-12, INFγ, and CXCL10 levels were measured in patient serum. Finally, the efficacy of the Ad5-IL-12 cytotoxic gene therapy in patients with recurrent prostate cancer was accessed by measuring patient survival.