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-inhuman 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 (10 11 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.

Inducible secreting TLR5 agonist CBLB502 enhances antitumor activity of CAR133-NK92 cells for colorectal cancer

“…Indeed, the induction of the proin ammatory cytokines GM-CSF and IL-6 has been veri ed to be TLR5-dependent and occurs in a dosedependent manner in response to CBLB502, a pharmacologically optimized agellin derivative, and Feinstein.,et al also suggested that G-CSF and IL-6 might be candidate biomarkers of CBLB502 e cacy in vivo [44]. This idea was further supported by the work of Eremina., and colleagues, who reported that Mobilan (consisting of human Toll-like receptor 5 and CBLB502) induced elevation of G-CSF and IL-6 levels [45]. Beyond that, our results also indicated that IL-7 production by CAR133-i502-NK92 cells was elevated; and IL-7 is critical in promoting cell proliferation and inhibiting apoptosis of NK cells [46,47],…”

“…In this study, pathological examination of mouse tissues, including the colon, brain and stomach, did not reveal signs of adverse events, suggesting that the CBLB502 secreted by the CAR133-NK92 cells enhanced antitumor activity and without toxicity to normal tissue. In a recent study, Eremina and Gudkov reported that Mobilan, which consists of human Toll-like receptor 5 (hTLR5) and CBLB502, was safe and well tolerated at all tested doses in early-stage prostate cancer patients [45]. Taking this recent study into account, it should be noted that the CBLB502 secreted by the CAR133-NK92 cells demonstrated satisfactory safety and tolerability in vivo.…”

TLR Agonists as Vaccine Adjuvants Targeting Cancer and Infectious Diseases

“…The vector drives the expression of a self-activated TLR5 signalling cassette, which comprises human TLR5 and a secreted derivative of the natural TLR5 ligand flagellin from Salmonella species [ 42 ]. In 2020, the first completed clinical study of Mobilan as a drug candidate for immunotherapy in prostate cancer patients demonstrated safety, tolerability and elevation of prostate-specific antigens and cytokine levels and increased lymphoid infiltration into prostate tissue [ 43 ]. Mobilan was thereby capable of maintaining strong NF-κB signalling and led to the recruitment of innate immune cells, including neutrophils and NK cells.…”

Toll-like receptor-targeted anti-tumor therapies: Advances and challenges

“…In preclinical prostate cancer models, Mobilan displayed promising therapeutic efficacy (276).In phase I clinical trial NCT02654938, Mobilan was used intratumorally to treat prostate cancer; no results are available yet. A similar study showed Mobilan was well-tolerated in prostate cancer patients (278); however, more data is needed to verify its clinical benefit. TLR 7 and TLR 8 TLR 7 and 8 serve as important sentinels in response to infection, which makes them irreplaceable in the activation of mammalian innate immune cells (279).…”