Geneos Therapeutics is gearing up to initiate a Phase 1/2 trial of a triple immunotherapy combination, including its patient-specific cancer vaccine GNOS-PV02, in people with advanced hepatocellular carcinoma (HCC), the most common type of liver cancer.
The open-label GT-30 trial (NCT04251117) is planning to include 12 HCC patients to test a combination of GNOS-PV02, the immune system modulator INO-9012, and the immune checkpoint inhibitor Keytruda (pembrolizumab).
The three treatments all work to boost immune system responses, but do so through distinct mechanisms.
“Checkpoint inhibitors and other immunotherapies have advanced the cancer treatment field and have had a significant impact on clinical outcomes,” Mark Yarchoan, an investigator of the GT-30 study, said in a press release. “However, every patient’s tumor is unique and in order to further improve outcomes, I believe that personalized approaches are critical.”
GNOS-PV02 is a personalized cancer vaccine that elicits strong immune responses against cancer cells bearing mutated cancer proteins. It uses a system called the GT-EPIC Neoantigen-Targeting Platform, licensed from Inovio Pharmaceuticals, which is able to perform DNA sequencing on tumor cells for each patient, allowing for the identification of specific mutations that are present on the patient’s tumor and not in the patient’s normal genome.
The mutated proteins are referred to as neoantigens, as they are newly formed and lead to a response from the immune system, which recognizes them as “foreign.”
Once the specific mutations are identified, DNA sequences with these mutations are placed onto a small molecule of DNA, called a plasmid. These patient-specific plasmids are inserted directly into healthy cells of the patients, and those cells will produce mutated proteins based on the instructions encoded in the plasmid.
By increasing the production of these specific mutant proteins, GNOS-PV02 also increases the activation of T-cells (immune cells with the ability to eliminate tumors) against those proteins, essentially working like a vaccine.
Keytruda, developed by Merck (known as MSD outside the U.S. and Canada), is an immune checkpoint inhibitor that prevents cancer cells from evading the immune system. It does so by preventing the PD-1 receptor — a protein found on the surface of T-cells — from interacting with other proteins in cancer cells, an interaction that prevents T-cells from seeing cancer cells as threats.
Keytruda is approved for advanced HCC patients who received prior treatment with Nexavar (sorafenib), but its efficacy is limited, with 17% of patients responding to treatment.
Finally, INO-9012 is designed to bolster the activation and expansion of immune T-cells. Licensed from Inovio, it is also a DNA plasmid, but codes for a protein called interleukin-12 (IL-12), which is required for T-cells to exert their function.
“I’m excited about this clinical trial utilizing Geneos’ innovative personalized treatment approach in combination with an approved immunotherapy for the treatment of advanced HCC,” Yarchoan said. “HCC is one of the fastest growing cancers in the U.S., and a significant unmet need exists to find more efficacious treatments.”
The upcoming clinical trial, slated to begin in March 2020, will take place at three U.S. sites: Johns Hopkins Hospital, Icahn School of Medicine at Mount Sinai, and Auckland Clinical Studies. It will include patients who failed first-line treatment with a tyrosine kinase inhibitor such as Nexavar, or who are intolerant to such treatments.
Participants will receive the three immunotherapies. Keytruda will be given as an intravenous (into-the-vein) injection, while GNOS-PV02 and INO-9012 will both be administered via skin injection.
This injection uses a proprietary device (also licensed from Inovio) called CELLECTRA 2000, which enhances the efficiency of injection and vaccine uptake. This is achieved by a process called electroporation, in which a small electrical pulse is generated to introduce temporary pores in the target cells.
The primary goals of the study are to measure safety and immune system activity against the neoantigen targets over a two-year period after the treatment is initiated. To measure for safety, researchers will monitor for any adverse reactions.
Secondary goals include response to treatment, duration of response, proportion of patients achieving at least stable disease, time to disease progression or death, and overall survival.
“We are excited about this first clinical trial for the Geneos GT-EPIC neoantigen-targeting platform,” said Niranjan Y. Sardesai, MD, the founder and CEO of Geneos. “This trial will seek to demonstrate that Geneos can produce personalized neoantigen-targeting immunotherapies in a clinically meaningful time frame, which drive strong T cell responses … and that these immunotherapies can enhance the efficacy of a PD-1 inhibitor alone.”