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

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.

Keywords: adenoviral vector; immunotherapy; intratumor injection; mobilan; prostate cancer.

Figure 1. Schematic illustration of the mechanism of action of Mobilan resulting in activation of antitumor immune responses.

Figure 2

Study design for the first-in-human Phase I clinical trial of Mobilan (A) and schedule of study stages (B). See text for details.

Figure 3. Titer of anti-502s antibodies in peripheral blood plasma of patients injected with Mobilan (M-VM3) or placebo.

The anti-502s antibody titer on Day 29 after IP/placebo injection on Study Day 1 is shown normalized to the baseline titer measure on Day 1 before injection (set at 100%. Mean values ± SEM are shown. ^* P value < 0.05 (ordinary 1-way ANOVA test) shows comparison of normalized Mobilan value to normalized placebo value.

Figure 4. Effect of Mobilan injection on plasma levels of cytokines.

G-CSF, IL-6 and IL-8 were measured in plasma samples collected from study subjects at the indicated times before or after Mobilan/placebo injection on Study Day 1 using specific ELISA assays. Mean values ± SEM for all cohorts combined are shown. P value < 0.05 (way ANOVA test). Extreme values (≥ 10-fold higher than the group mean) reflecting individual patient variability were excluded from the analysis. ^* P value < 0.05 (multiple t-test). EoS = end of study visit.

Figure 5. Effect of Mobilan injection on total PSA levels in the serum of prostate cancer patients (ng/mL).

PSA levels were measured by chemilumescent assay in serum samples collected at the indicated timepoints relative to Mobilan or placebo injection on Study Day 1. Mean values ± SEM for all cohorts combined are shown. Day 29/EoS data are not shown because some study subjects underwent RPE before that visit (which had a significant effect on PSA levels), while other subjects did not have surgery before Day 29. No study subjects had RPE surgery before Day 15. ^* P value < 0.05.

Figure 6. Irani scores for degree of lymphoid infiltration (left) and aggressiveness of lymphoid infiltration (right) assigned to prostate tissue samples collected during RPE from study subjects treated with Mobilan (M-VM3) or placebo.

RPE took place after Day 15 according to IP prescription. Mean ± SEM for all cohorts combined is shown. ^* P value < 0.05 (multiple t test).