A phase I clinical trial of oncolytic adenovirus mediated suicide and interleukin-12 gene therapy in patients with recurrent localized prostate adenocarcinoma

• Published in: PloS one Vol. 18; no. 9; p. e0291315
• Main Authors: Nyati, Shyam, Stricker, Hans, Barton, Kenneth N., Li, Pin, Elshaikh, Mohamed, Ali, Haythem, Brown, Stephen L., Hwang, Clara, Peabody, James, Freytag, Svend O., Movsas, Benjamin, Siddiqui, Farzan
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 15.09.2023; Public Library of Science (PLoS)
• Subjects: Adenocarcinoma; Adenocarcinoma - therapy; Adenoviridae; Adenoviruses; Antigens; Biology and life sciences; Cancer; Cancer therapies; Care and treatment; Clinical trials; Complications and side effects; CXCL10 protein; Cytokines; Cytotoxicity; Diagnosis; Diseases; Dose dependency; Evaluation; Gene therapy; Genes; Genes, Transgenic, Suicide; Genetic aspects; Genetic research; Genetic Therapy - adverse effects; Health aspects; Humans; Immune system; Interleukin 12; Interleukin-12 - genetics; Interleukins; Kinases; Leukocytes, Mononuclear; Leukopenia; Male; Medicine and Health Sciences; Oncolysis; Oncolytic Virotherapy; Patient outcomes; Patients; Peripheral blood mononuclear cells; Product development; Prostate; Prostate cancer; Prostatic Neoplasms - therapy; Radiation therapy; Relapse; Replication; Research and Analysis Methods; Suicidal behavior; Suicide; Suicide genes; Toxicity; γ-Interferon; United States
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0291315

In a phase I dose escalation and safety study (NCT02555397), a replication-competent oncolytic adenovirus expressing yCD, TK and hIL-12 (Ad5-yCD/ mut TK SR39 rep -hIL-12) was administered in 15 subjects with localized recurrent prostate cancer (T1c-T2) at increasing doses (1 × 10 10 , to 1 × 10 12 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 10 12 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. PBMC analysis revealed immune system activation after gene therapy in cohort 5. The PSA doubling time (PSADT) pre and post treatment has a median of 1.55 years vs 1.18 years. This trial confirmed that replication-competent Ad5-IL-12 adenovirus (Ad5-yCD/ mut TK SR39 rep -hIL-12) was well tolerated when administered locally to prostate tumors.