TLR5 Genetic Variants May Help Predict Response to Entolimod

A specific genetic signature may predict how solid tumor cancer patients respond to the immunotherapeutic drug entolimod in terms of tumor shrinkage as well as potentials side effects from the drug.

This investigational agent is being developed by Cleveland BioLabs, Inc. for two indications: an anticancer treatment and a pivotal-stage radiation countermeasure for acute radiation syndrome (ARS).¹ Now, researchers at Roswell Park Cancer Institute (RPCI) have found that the characteristics of genetic variants in human toll-like receptor 5 (TLR5) may predict antitumor responses to entolimod.²

RPCI Researchers reported at the American Association for Cancer Research (AACR) Annual Meeting (held April 18-22, 2015 in Philadelphia) that TLR5 is expressed on a wide variety of tumors. They found that the induction of TLR5 signaling exhibits antitumor activities through the mobilization of innate and subsequent adaptive antitumor immune response.

TLR5 is a type 1 transmembrane receptor involved in the first line of defense against invading bacterial pathogens expressing flagellin. TLR5 also plays a critical role in early immune response, and is expressed in a wide variety of tumors and in normal tissues at common sites of metastasis.

Entolimod is a pharmacologically optimized flagellin of Salmonella, and it is the first TLR5 agonist to enter clinical trials. Entolimod binds to TLR5, and activates NF-kB and other signaling pathways to elicit antitumor activity. Previous studies have shown that the antitumor activity of entolimod is dependent on the expression of functional TLR5 on tumors.

Study investigator Araba Adjei, PhD, who is an Associate Professor of Oncology in the Department of Pharmacology and Therapeutics at Roswell Park Cancer Institute in Buffalo, said that genetic variations in TLR5 could predict how patients will respond to treatment with entolimod in terms of efficacy and development of potential adverse effects from use of the drug.

Dr. Adjei and colleagues evaluated the effect of nine of the TLR5 variants in response to entolimod, and found a wide range of variations in TLR5 protein levels along with corresponding ranges in activity. The researchers said this suggests the possibility for variations in anticancer activities when patients demonstrating these TLR5 variants are treated with entolimod.

The US Food and Drug Administration (FDA) has granted Fast Track and Orphan Drug status for entolimod for reducing the risk of death following a potentially lethal dose of total body irradiation during or after a radiation disaster. A phase I study of entolimod in patients with advanced solid tumors at RPCI has completed recruitment, and a second phase I study of entolimod in patients with advanced cancer is currently ongoing in the Russian Federation, according to Cleveland BioLabs, Inc.

References:

• Cleveland BioLabs, Inc. (2015). Entolimod (CBLB502) Biodefense.
• Roswell Park Cancer Institute. (2015). TLR5 Genetic Variants May Predict Antitumor Responses to Entolimod.