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Cancer, Meet Your Newest Opponent

Immune checkpoint therapies received a lot of airtime at American Society of Clinical Oncology (ASCO) meeting in Chicago last week. The release of promising new clinical data has everyone buzzing about more cures for more cancers as a follow-on to last year’s race to the market.

The hype seems to be justified. Simply put, these new therapies thwart one of cancer’s most sly moves: their ability to evade killer T-cells. This slight-of-hand maneuver has limited a patient’s own T-cells to fight off tumors, and the efficacy of cancer vaccines/treatments that rely on a fully functioning immune system. This WEEKLY explains how immune checkpoint therapies get the job done. Read on and learn which of these therapies are on the market and which are barreling down the clinical pipeline.

TERM OF THE WEEK: IMMUNE SYSTEM CHECKPOINT

In order to prevent autoimmune disorders, our immune system has evolved “checkpoints”—proteins on immune cells (such as T-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 cover of darkness. Immune system checkpoint therapies take away the control of the switch before cancer has a chance to flip it.

CHECKING OUT CTLA-4

CTLA-4 is a checkpoint 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 Holmes asleep.

Bristol Myers Squibb’s (New York, NY) Yervoy is a monoclonal antibody that targets the CTLA-4 proteins and prevents cancer from hitting the T-cell off switch. Yervoy was the first checkpoint inhibitor drug approved by the FDA in 2011 and is indicated for melanomas that cannot be removed by surgery.

PD-1 AND PDL-1 Straight TO THE POINT

Two other notable checkpoint proteins are PD-1 and PDL-1, the Dr. Watsons of this story. PD-1 is another T-cell surface protein switch; its inhibitory activity is turned on when it meets the PDL-1 protein on the surface of host cells. Some cancers have increased numbers of PDL-1  receptors, making these cancers incognito experts.

In September 2014, the FDA granted accelerated approval to the PD-1 receptor inhibitor Keytruda developed by Merck (Kenilworth, NJ) to treat patients with advanced melanoma. This approval was followed quickly by the December approval of Bristol-Myers Squibb’s (New York, NY) PD-1 inhibitor Opdivo, also for advanced melanoma, and in March of this year for non-small cell lung cancer.

One potential advantage of PD-1 (or PD-L1 inhibitors) over CTLA-4 inhibitors: PD-1/L1 inhibitors may have fewer side effects. PD-1/L1 inhibitors seem to primarily activate T-cells already present in tumor tissues. CTLA-4 inhibitor drugs have over-activated the immune response—resulting in autoimmune-like symptoms.

The talk of ASCO were the immune checkpoint therapies in the pipeline:

PD-1 & PDL-1 Inhibitors In Development

AFTER THE CHECKPOINT

Oncologists are excited about the new checkpoint inhibitors for two main reasons:

  • They are proving to have longer-lasting efficacy, even compared to the highly effective, targeted monoclonal antibodies. Once activated by checkpoint therapy, the immune system can evolve and change with the cancer, unlike static therapies.
  • They promise to fight a range of different cancers, though their efficacy will vary between different subcategories of patients.

As with all medicines, physicians want to identify the patients most likely to respond to a particular drug. For example, the obvious criteria for giving a patient a PD-1 inhibitor drug is the over expression of the PD-1 protein on the surface of his tumor cells—however, this may not be the only way to identify patients who may benefit. Early studies indicate that genetic signatures of tumors may also help predict who will respond well to PD-1 inhibitors. The diagnostics company NanoString Technologies (Seattle, WA) is developing a genetic test to predict who is most likely to benefit from checkpoint inhibitor therapies. Another possibility is simply looking at tumor biopsies to determine if T-cells are already present—increasing the likelihood that turning them on will impact the tumor. With the buzz getting louder, its only a matter of time before we see these intriguing drugs take on the fight against cancer.

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