It’s not so elementary my dear watson

PLAYING DETECTIVE WITH CHECKPOINT THERAPIES

Over the past two weeks we’ve discussed cancer immunotherapies that involve training T-cells (the detective warriors of our immune system) into seeking and destroying cancer cells.

This week we’ll take a look into another approach that has been creating a lot of recent excitement: checkpoint inhibitor drugs. Simply put, investigators believe they have figured out a way to dismantle the mechanism used by cancer cells to stay hidden from T-cells.

CTLA-4 is a protein on the surface of T-cells that acts as an “off switch” for the sleuthing T-cells. It signals them to remain in a resting state, kind of like Sherlock lacking his investigative instincts. Yervoy (Bristol Myers Squibb) is a monoclonal antibody that targets these CTLA-4 proteins and prevents them from sending the “off switch signal”, which allows the T-cells to turn “on” their remarkable ability to sniff out disguised cancer cells.

Yervoy was the first checkpoint inhibitor drug approved by the FDA (2011), and is used to treat melanomas that can’t be removed by surgery.

Two other notable checkpoint proteins are PD-1 and PDL-1, the Dr. Watsons of this story. PD-1 is another inhibitory protein on the surface of T-cells; its inhibitory activity is turned on when it meets the PDL-1 protein on the surface of host cells. Some types of cancer cells have increased amounts of PDL-1 on their surface – making them experts at evading the immune system.

Fear not for Dr. Watson is on the case and a number of companies, including Bristol Myers Squibb, Roche, and Merck, are developing inhibitor drugs for PD-1 and PDL-1. The treatment of a variety of cancers, including melanoma, kidney cancer, and non-small cell lung cancer could soon be less of a mystery and more of a reality.

 

ON THE CASE

While PD-1 or PDL-1 checkpoint inhibitor drugs have yet to be approved by the FDA, there’s momentum behind these immunotherapies. In a promising development Bristol Myers Squibb has developed a PD-1 inhibitor recently approved in Japan for the treatment of melanoma. The drug is marketed by Japanese partner Ono Pharmaceutical under that brand name Opdivo.

In May, Roche won the FDA’s coveted breakthrough therapy designation for their PDL-1 program, potentially putting it on an inside track at the agency, which has been hurrying along new medicines in the pipeline.

THE FLIP SIDE

Over-riding immune system checkpoints could potentially have some negative effects-–namely the activation of autoimmune-like symptoms in patients.

One reason researchers are so excited about PD-1 inhibitor drugs is the clinical data, so far, indicates fewer adverse reactions than those encountered with CTLA-4 inhibitor drugs. PD-1 inhibitors work by targeting a mechanism common to many cancers – “cloaking” their sinister activities behind the PD-1 receptor. Many are hopeful PD-1 inhibitors will be broadly effective against a range of cancers and have safer profiles.

COCKTAIL FODDER

Preclinical studies suggest that PD-1 inhibitors may also be effective in treating HIV infection. HIV uses infected T-cells to disable the immune system. Human clinical trials for the HIV indication are in planning stages.

 

TERM OF THE WEEK: IMMUNE SYSTEM CHECKPOINT

In order to prevent autoimmune disorders, our immune system has evolved “checkpoints” – proteins on immune cells that need to be switched “on” or “off” in order to start the appropriate immune response.

Some cancer cells have cleverly evolved ways to exploit these checkpoints and proliferate under the guise of mystery. Immune system checkpoint therapies thwart the criminal cancer cells early on by taking control of the switch before its flipped.