A phase I trial of adenovector-mediated delivery of interleukin-2 (AdIL-2) in high-risk localized prostate cancer

Abstract

Preclinical studies demonstrate that intratumoral delivery of adenovirus expressing IL-2 eradicates pre-established tumors in mice and confers immune protection from rechallenge. To explore the activity of AdCAIL-2 in prostate cancer, a Phase I clinical trial was conducted in patients with localized disease and Gleason score 47 or prostate-specific antigen (PSA) 410 plus Gleason score 7. A total of 12 patients were injected 4 weeks prior to prostatectomy in a dose-escalation study at doses of 10 9 , 5 Â 10 9 and 10 10 PFU of virus. No dose-limiting toxicity was observed. Side effects included perineal discomfort, hematuria, flu-like symptoms in two patients and urinary hesitancy in one patient. Pathology demonstrated an inflammatory response consisting predominantly of CD3+CD8+ T lymphocytes with areas of tumor necrosis. Intracellular cytokine staining of tumor-infiltrating lymphocytes demonstrated increases in both g-interferon and IL-4 secreting T cells after vaccination. PSA levels fell in five of five evaluable patients treated at the lowest dose (mean decline of 33.3%, range 17-69%). At higher doses, PSA values initially increased after injection, then fell to baseline prior to surgery. This trial demonstrates the feasibility and safety of intraprostatic adenovectormediated IL-2 gene delivery.

Therapeutic effects of adoptive splenocyte transfer following in situ AdIL-12 gene therapy in a mouse prostate cancer model

“…It may also be useful to use this method of delivery, that is, adenoviral vector-mediated IM injection to introduce other stimulatory cytokines that have been previously shown to promote antitumor responses in the clinic, for example, IL-2. 32,33 Our results have unique significance for neo-adjuvant and adjuvant immuno-gene therapy applications with standard treatments for presumed localized disease, that is, radical prostatectomy and radiation therapy. They also have significance for patients who may receive in situ immuno-gene therapy for recurrence after radiation therapy 13 as a way to enhance or prolong a favorable response.…”

Attenuated Salmonella typhimurium with IL-2 Gene Reduces Pulmonary Metastases in Murine Osteosarcoma

“…Intravenous injections of liposomes containing IL-2 cDNA are effective in treating pulmonary metastases in canine spontaneous osteosarcomas, and have produced complete remission in some pediatric cases [6,30,32]. However, the highly toxic effects of intravenous IL-2 therapy has required investigators to alter the frequency, method of delivery and dosing, limiting the benefits of and response to the therapy [22,30,32,36]. Intravenous interleukin-2 therapy requires multiple injections for results similar to those seen with a single oral dose of attenuated SalpIL2.…”

Gene therapy for malignant mesothelioma: beyond the infant years

“…19 Moreover, clinical trials with intrapleural IL-2 administration have been conducted for mesothelioma, and other tumors, and have yielded encouraging results. [20][21][22][23] In our study, six mesothelioma patients were treated with the vaccinia virus recombinant. No systemic or local toxicities were observed, and, despite antibody responses, vaccinia virus-IL-2 mRNA gene expression persisted in tumor biopsies for up to 3 weeks.…”