Under the Microscope: Targeting Lung Cancer with a One-Two Punch

Immunotherapies harness a patient’s own immune system to detect and destroy cancer cells. When they work, they can work wonders. However, for unknown reasons, 70-80 percent of lung cancers are not cured by immunotherapy.

With V Foundation support, researchers are working hard to improve those odds. Christine Fillmore Brainson, an assistant professor at the University of Kentucky’s College of Medicine, is exploring additional treatments that could make cancer cells more vulnerable to immunotherapy.

“We know immunotherapy will work in some cases,” explained Brainson, who received a V Scholar award for her work. “But is there something we can combine it with to make it work in more cases?”


A complex cancer

Despite tremendous progress in cancer treatment overall, lung cancer—the worldwide leader in cancer deaths—has maintained a stubbornly poor prognosis. The subtype known as squamous cell lung cancer has a particularly devastating outlook, with just 15 percent of patients surviving five years after their diagnosis.

One of the reasons for this poor prognosis is that squamous cell tumors tend to have a large variety of cancer cells within them. Because most cancer drugs work by targeting one type of cell, treating squamous cell carcinoma can be like a game of whack-a-mole, with drugs knocking out one type of cancer cell but allowing others to grow unchecked. Survival chances are especially bad if a patient’s biopsy shows a high number of neutrophils, a type of white blood cell, in the tumor.


Promising early results

Brainson and her team propose a new approach: a one-two punch that first uses a drug to make cancer cells vulnerable to immunotherapy, followed by a full-force attack that marshals the body’s immune system to fight the tumor.

For the first punch, the team is using EZH2 inhibitors, experimental cancer drugs designed to inhibit an enzyme that helps cancer cells grow. In their experiments with mouse models of squamous lung cancer, the EZH2 inhibitor has shown two very promising results so far. First, the tumor cells ramp up their expression of a marker that makes them more visible, and thus more susceptible to immunotherapy. Second, mice treated with the drug have changes in the neutrophils in their tumors, which may also make immunotherapy more effective.

“That’s what we’re really excited about,” said Brainson. “We’re targeting one of the cell types—neutrophils—that might be disrupting immunotherapy in the first place. If we can make the tumors more susceptible to immunotherapy, that could allow us to kill the cancer at its root.”


The road ahead

This good news comes in just the first year of a multiyear project designed to find out whether Brainson’s combination therapy can improve squamous cell carcinoma outcomes. The team hopes that within a few years, they’ll be ready to move into human clinical trials. Before that can happen, they are working to understand how the combination works at the molecular level, as well as any potential side effects.

“The V Foundation really helped get this project off of the ground, and without it we wouldn’t be in a position to gain insight into what’s really happening in the cancer cells,” said Brainson. “Using drug combinations has become very popular, but understanding how to use them correctly and which types of tumors are going to respond well to the combinations is how we’re going to get the best responses.”

Brainson is closely watching a similar study in bladder cancer, which shares some similarities to squamous cell carcinoma. The results of that trial, especially concerning neutrophils, could bode well for her future clinical trials—and mean good news for lung cancer patients facing a discouraging prognosis.