Booster Shot
The case was dire: An inoperable sarcoma had invaded 16-year-old John Ficken’s abdominal wall, pelvis, and bladder. The boy’s belly protruded with the growth, and the pain was unrelenting. Yet Mr. Ficken’s young surgeon and oncologist, William Coley, harbored cause for optimism: an eponymous (and experimental) bacterial cocktail intended to jumpstart his patient’s immune system and eradicate the cancer. Over the course of four months, the New York City physician injected Mr. Ficken’s tumor with an increasingly potent dose of Coley vaccine. Each treatment induced inflammation, chills, and fever, but slowly, the tumor shrank. By the time Mr. Ficken’s treatment ended in May 1893, the cancer had shrunk by 80 percent. As that summer drew to a close, the tumor was barely perceptible. Mr. Ficken lived another quarter century, until a heart attack killed him in 1919.
A century after Dr. Coley’s pioneering work was eclipsed by sterile surgical techniques, radiation, and chemotherapy, scientists have again turned their attention to the role of the immune system in fighting cancer. One of the latest immunotherapies to reach the market is nivolumab, a drug approved by the FDA for the treatment of patients with advanced squamous non-small cell lung cancer, or NSCLC.
Nivolumab rehabilitates the immune system’s delicate balance by restoring activity of the T cells. Specifically, the drug disables the PD-1 protein, which suppresses T cell activity. When this “checkpoint” protein is inhibited, T cells can go about their business.
“Groundbreaking” and “revolutionary” often overstate the case, says Naiyer A. Rizvi, MD, director of thoracic oncology and immunotherapeutics, but the words truly apply to the impact of the new immunotherapy agents that target the PD-1 pathway for NSCLC.
Work by Dr. Rizvi was key to approval of nivolumab for squamous lung cancer. “When I first started treating patients with nivolumab in 2008, it was hard to imagine how dramatically this could help patients who were resistant to all of our standard treatments,” says Dr. Rizvi. “We have some patients who are still alive many years after taking this drug, with no evidence of Booster Shot cancer. This has never been seen with standard lung cancer treatment.”
While some patients with NSCLC respond well to PD-1 inhibitors, others do not. Dr. Rizvi and his former colleagues at Memorial Sloan Kettering Cancer Center thought that the cancers that had accumulated the most DNA damage were more likely to have worn out the immune system and would likely be helped the most by PD-1 inhibitors.
They tested their hypothesis by sequencing tumor DNA from both responders and nonresponders to treatment with pembrolizumab, a PD-1 inhibitor. Among their findings was that patients with extensive DNA damage were far more responsive to treatment than those with less DNA damage. “We were able to use advances in sequencing technology to study the entire exome of tumors from patients with NSCLC who were treated with pembrolizumab. We found that the more genetically damaged the tumor was, the more likely the patient was to respond to PD-1 inhibitors.
“This is an important first step toward being able to predict who will respond to PD-1 inhibitors,” says Dr. Rizvi, “and could be a new way to think about precision medicine based on the sequencing of tumor DNA.”
https://www.youtube.com/watch?v=-nOS7uhX8VQ
This is a summary of research published in Lancet Oncology, March 2015, and Science, April 3, 2015.