Partnership yields new immunotherapy drug and a clinical trial

A new drug that’s based on MD Anderson research and designed to rev up an immune system assault on cancer has advanced to clinical trial both as a single agent and in combination with another immunotherapy to double-team late-stage solid tumors.

GlaxoSmithKline (GSK) worked with a platform of MD Anderson’s Moon Shots Program to prepare this new approach to immune-oncology for clinical trial. Moon shots are designed to accelerate the development of new treatments based on scientific discoveries.

GSK announced the clinical trials for GSK3174998 in a joint news release with Merck, which makes Keytruda, the other drug in the combination. Both drugs are humanized monoclonal antibodies that plug into proteins on the surface of T cells, the adaptive immune system troops customized to find and destroy cells bearing specific targets, or antigens.

GSK3174998 connects with and activates OX40, stimulating immune attack and memory functions while hindering regulatory T cells that suppress immune response. Keytruda blocks activation of PD1, a checkpoint molecule that shuts down T cell attack.

This double-whammy effect could be a powerful combination, notes Carlo Toniatti, M.D., Ph.D., executive director of Oncology Research for Biologics & Immunotherapy Translation (ORBIT), a moon shots research engine that collaborated with GSK to develop the OX40 drug.

“It’s great that GSK worked out an agreement with Merck to launch the combination trial,” Toniatti says. “It makes scientific sense and has the potential to be very good for patients.”

After GSK and MD Anderson reached a collaboration and licensing agreement in late 2012, Toniatti and colleagues worked with the company to produce data for an Investigational New Drug (IND) application required by the Food and Drug Administration for a drug to proceed to phase I clinical trial.

“We generated preclinical data demonstrating the efficacy of the antibody,” Toniatti says. “And we were the first to show convincingly that OX40 and PD1 is a good combination. It was a real collaboration, ORBIT and GSK labs working together.”

GSK leads the multi-center clinical trial and all further clinical development. MD Anderson will participate as a site in the trial, which hasn’t opened at the institution. In an additional connection, MD Anderson’s immunotherapy platform will conduct exploratory immune profiling of tumor samples from the trial to identify potential new biomarkers that might guide treatment.

Keytruda is approved by the FDA to treat advanced melanoma and lung cancer. It and other PD1 inhibitors are advancing in clinical trials against other cancers.

Combinations are key

No drugs targeting OX40 have earned FDA approval. While checkpoint blockade drugs have shown strong results for some patients, combination therapies are considered the key to extending and improving outcomes for more patients.

The GSK agreement led to the development of ORBIT, a spin-off of MD Anderson’s Institute for Applied Cancer Science. Toniatti notes development of antibody-based drugs is time-consuming and takes certain types of expertise, so MD Anderson decided to devote resources to a platform dedicated to monocloncal antibodies and other biotherapeutic drugs.

GSK licensed the OX40 agonist antibodies discovered by Yong-Jun Liu, M.D., Ph.D., former professor and chair of Immunology at MD Anderson, in one of the largest such agreements ever made by the institution. Liu is vice president and chief scientific officer of the Baylor Research Institute in Dallas.

Over the life of the agreement, MD Anderson could earn up to $335 million in payments from GSK along the way to FDA approval. MD Anderson also would be entitled to royalties on products developed out of the collaboration.

ORBIT is developing another antibody invented at MD Anderson, one that targets acute myeloid leukemia, under an agreement with Astellas Pharma, Inc.