First-in-human study of anticancer immunotherapy drug candidate mobilan: safety, pharmacokinetics and pharmacodynamics in prostate cancer patients.

Natalia V Eremina,Dmitry Y Pushkar,Vadim L Mett,Vasily I Kazey,Sergey V Mishugin,Roman V Leonenkov,Andrei V Gudkov

doi:10.18632/oncotarget.27549

Natalia V Eremina, Dmitry Y Pushkar + Show 5 more

Open Access

https://doi.org/10.18632/oncotarget.27549

Copy DOI

Abstract

Toll-like receptor 5 (TLR5) controls endogenous immune responses to pathogens and is a promising target for pharmacological stimulation of anti-tumor immunity. Mobilan is an innovative gene therapy agent consisting of a non-replicating bicistronic adenovirus directing constitutive expression of human Toll-like receptor 5 (TLR5) and the secreted flagellin-based TLR5 agonist, 502s. In mice, Mobilan injection into prostate tumors resulted in autocrine TLR5 signaling, immune system activation, and suppression of tumor growth and metastasis. Here we report a first-in-human placebo-controlled clinical study of Mobilan aimed at evaluating safety, tolerability, pharmacokinetics and pharmacodynamics of a single intra-prostate injection of Mobilan in early stage prostate cancer patients. Mobilan was safe and well-tolerated at all tested doses; thus, the maximum tolerated dose was not identified. Injection of Mobilan induced signs of self-resolving inflammation not present in placebo-injected patients, including transient elevation of PSA and cytokine (G-CSF, IL-6) levels, and increased lymphoid infiltration in prostate tissue. The highest dose of Mobilan (1011 viral particles) produced the best combination of safety and pharmacodynamic effects. Therefore, Mobilan is well-tolerated and induces the expected pharmacodynamic response in humans. These results support further clinical development of Mobilan as a novel immunotherapy for prostate cancer.

Highlights

Prostate cancer (PC) is the fourth most common type of malignant neoplasm in the world, being surpassed only by breast, lung and colorectal cancers
The trial was a single-blind, randomized, placebocontrolled phase I study aimed at evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of a single intra-prostatic injection of Mobilan in patients diagnosed with prostate cancer, with dose escalation
Thirty-four patients ranging in age from 53 to 74 years were screened for participation in the study

Summary

Introduction

Prostate cancer (PC) is the fourth most common type of malignant neoplasm in the world, being surpassed only by breast, lung and colorectal cancers. 1.3 million new PC diagnoses were made worldwide in 2018. In the United States (US), an annual incidence rate of ~170,000 makes PC the most common of all cancers in males (excluding nonmelanoma skin cancers) [1]. Prostate cancer is the most common cancer among males in European countries, with a prevalence of 214 cases per 100,000 males [4]. In addition to its high incidence, PC accounts for a large proportion of all cancer-related deaths. PC ranks second among oncological diseases with respect to mortality in males worldwide [2, 3]

Objectives

Methods

Results

Conclusion