By Samantha Black, Ph.D.

September 5, 2019 -- A research team at Johns Hopkins University identified new therapeutic targets that will help increase the efficacy of current immunotherapies and reduce the side effects in patients with lung cancer. The results of this clinical study were published in The Journal of Clinical Investigation on September 4.

For patients with non-small cell lung cancer (NSCLC), evidence has been provided that immunotherapies such as immune checkpoint inhibitors (ICI) can be an effective form of treatment. ICI drugs blocks proteins, i.e. PD-1/PD-L1 & CTLA-4/B7-1/B7-2, made by some types of immune cells and some cancer cells. When these proteins are blocked, they elicit an immune response that enables T cells to kill cancer cells. However, activating the immune system can have unwanted side effects. A dangerous complication can occur where up to 19% of patients develop checkpoint inhibitor pneumonitis (CIP), a complication caused by inflammation of the lungs. Symptoms of this condition include: arthritis, colitis, endocrinopathies, and lung injuries. Patients with CIP must stop cancer treatment Despite the risk of CIP, ICI treatments are becoming a standard of care for the treatment of many kinds of cancers.

Researchers at Johns Hopkins University set out to study lung cells of NSCLC patients in order to pinpoint differences between patients with CIP and without. They collected tissues from the lungs of 12 NSCLC patients with CIP and six patients being treated with ICIs who hadn’t developed CIP. Samples were collected through bronchoalveolar lavage (BAL).

The team found that patients with CIP had higher levels of memory T cells: 10% more than patients without CIP. Moreover, the results showed that patients with CIP had decreased CTLA-4 and PD-1 expression within Treg population, suggesting an attenuated Treg suppressive phenotype promoting exuberant T cell responses. These findings support the idea that highly activated alveolar T cells with loss of a regulatory, anti-inflammatory Treg suppressive phenotype contributes to unchecked immune dysregulation observed in CIP.

The researchers also identified several therapeutic targets for patients with CIP in this study including: TNF-alpha, CD62L t cells and IL-1beta-expressing monocytes. This is just the beginning of understanding the role of CIP in lung cancers and more research is needed to ascertain how CIP impacts overall survival. Limitations of this study include are low sample size and the BAL testing may not be accurate due to sample location or tumor status.

This is the first study investigating the mechanism of dysregulated alvelolar immune dysregulation in patients with CIP. “Based on the cell types we found, our study suggests several new pathways that could be investigated as therapeutic targets,” says Karthik Suresh, MD, co-author of the study.



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