Melanoma Therapy: Are Immune Checkpoint Inhibitors the Answer?

Metastatic melanoma has historically been very difficult to treat.  Although patients with early stage melanoma have a good survival rate, the prognosis is far worse if the cancer has spread to remote areas of the body.  With the advent of new immunological therapies such as ipilimumab (marketed as Yervoy), the odds for metastatic melanoma seem poised to improve.

The immune system leads the body's fight against infection, attacking cells that are identified as foreign.  Cancer cells are often seen as foreign by the body, and so they can also be targets of the immune system.  Immunological therapy works by enhancing this ability to recognize and remove cancer cells.  High-dose interleukin-2 (IL-2) is one of the early immunological treatments.  Although it has a modest success rate, IL-2 also has severe side effects.  

Ipilimumab is the new immunological drug on the block, appearing after decades of minimal progress.  It is a monoclonal antibody that helps to increase the body's T cell population by blocking T cell inhibitors.  Drugs of this class are called immune checkpoint inhibitors.  T cells play a central role in immunity; they directly kill foreign cells, retain memory of previous infections in order to mount faster subsequent responses and aid other body cells in the fight against invaders.  By increasing the T cell population, the body's immune response is enhanced and better able to launch an attack against the melanoma cells.  

The 2011 Phase III clinical trial of ipilimumab showed impressive results.  The three-year survival rate almost doubled; it increased from 12% to 21%.
Only a subset of the tested patients, however, experienced improved results.  A preliminary study that was recently published in 'Cancer Immunology Research' may explain some of the variation in response.  VEGF is a protein produced by the body that is used to repair and grow blood vessels, and it also can suppress maturation of immune cells.  Researchers found that patients with a high blood level of VEGF also had a poor response to ipilimumab.  If this preliminary research is confirmed, it would enable physicians to determine which patients are likely to benefit from the therapy.

Bristol-Myers Squibb is now investigating combination therapies that use multiple different checkpoint inhibitors.  Just last year, the company published the results of a Phase I study that combined Yervoy with nivolumab, an immunological agent that blocks T cell inhibition in a different manner.  In this Phase I trial, the responding patients had an 80% tumor shrinkage rate.  In addition, the estimated one-year survival rate was an impressive 82%.  Combination therapy shows great potential.

There are, of course, side effects to ipilimumab.  When the immune system is augmented, healthy tissue may be targeted along with the cancer cells.  Rashes, colitis, liver toxicity, neurological symptoms and endocrine issues have all been reported.  The drug is powerful, and its use requires careful patient monitoring.

Other drug companies are developing their own drugs along these lines.  Merck, Roche and AstraZeneca are all working on new immunological agents.  If their research goes well, these options should reach the market over the next four to five years.  

Immune checkpoint inhibitors are an area of active research in the fight against melanoma.  As physicians learn more about these drugs and how to combine them, patients could benefit greatly.  Metastatic melanoma patients may finally be seeing some light on the horizon.