Laying the Foundation for New Approach to Treating ALK-Positive Lung Cancer

Juhi Kunde, MA, LUNGevity Science Writer

Some lung cancer patients respond well to treatment with checkpoint inhibitor immunotherapy, which allows the body’s immune system to identify and attack cancer cells. However, patients with ALK-positive lung cancer, a type of non-small cell lung cancer in which the driving oncogene is a fusion of the ALK tyrosine kinase gene with another gene (often EML4), have not seen significant benefits from checkpoint inhibitor immunotherapy. Patients with ALK-positive lung cancer are typically treated with tyrosine-kinase inhibitor (TKI) drugs. These are effective at controlling tumors initially, but the tumors inevitably develop resistance to the treatment and begin to grow unchecked.

“My laboratory hypothesized that something was blocking the immune system’s natural defense mechanisms in ALK-positive patients,” explains Raphael Nemenoff, PhD, professor of medicine at University of Colorado Anschutz Medical Center, whose laboratory is focused on understanding the molecular causes of lung cancer. “Through discussions with other colleagues and reading research papers, we started to think that the complement pathway, a part of the innate immune system that regulates the adaptive immune response, should be investigated further.  Complement activation can result in the killing of infected cells, but also leads to chronic inflammation that could actually be helping cancer cells thrive in ALK-positive patients.”

Chemical compounds to inhibit the immune complement pathway are often used to reduce inflammation in patients with kidney disease. Studies from Dr. Nemenoff’s lab and others using genetic mouse models also suggested that tumor cells could be benefiting from the inflammation caused by the immune complement pathway. 

Dr. Nemenoff and his team decided to test this idea with a chemical compound that blocks complement activation. The team tested this agent in mouse models of ALK-positive lung cancer to determine if blocking the immune complement pathway could be a useful approach for treating patients with ALK-positive lung cancer.

“The results were very positive. We were able to inhibit the immune complement pathway using a chemical compound. We also used a different approach to inhibit it genetically. In both cases, the ALK-positive lung cancer models showed significantly reduced tumor growth when the immune complement pathway was targeted,” explains Dr. Nemenoff. “Of course, more research is needed here, but this is potentially the key to a new approach for treating ALK-positive lung cancer.” 

This work earned Dr. Nemenoff and his team a 2018 research grant funded by ALK-Positive—a group of more than 1,800 ALK-positive lung cancer patients and their caregivers in 42+ countries—to continue working to understand the mechanisms of this innovative approach to treating ALK-positive lung cancer.

“Because the percentage of non-small cell lung cancer patients with ALK-positive lung cancer is about 5%, there is a very real risk that the general body of lung cancer research might not focus on their specific cancer type,” notes Dr. Nemenoff. “That is why it is so important that nonprofits like LUNGevity and the ALK Positive community continue to raise funds and raise awareness, so that the research projects that are important to them can progress.”

Dr. Nemenoff and his team are continuing to study the underlying mechanisms of the complement pathway in ALK-positive lung cancer.  In addition, they are studying several pharmaceutical agents being developed to disrupt portions of the complement pathway. “The chemical compound that we used in the laboratory experiments is not suitable for people, so we are currently working to identify the most promising compounds to test in a phase 1 clinical trial,” explains Dr. Nemenoff. The team is hypothesizing that using a targeted chemical inhibitor of the complement pathway will reduce side effects and help patients retain more immune system function during treatment.  In addition, studies are underway to examine the frequency of complement activation in human ALK positive tumors, with a goal of developing rational strategies for patient selection. 

“We are working as quickly as we can to get the clinical trial in place,” notes Dr. Nemenoff. “We have an opportunity, here and now, to do research that could save lives, so we are making sure every day counts.”

 

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Juhi KundeJuhi Kunde, MA, is a science writer for LUNGevity.

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