Cancer immunotherapy responses in the clinic: T cell revival as predictor

In lung cancer patients who were taking immunotherapy drugs, testing for revived immune cells in their blood partially predicted whether their tumors would shrink. The results were published online by PNAS on April 26.

This finding comes from a small study of 29 patients, who were being treated at Winship Cancer Institute of Emory University with drugs blocking the PD-1 pathway, also known as checkpoint inhibitors.

The study supports a straightforward idea: if tumor-specific CD8 T cells appear to respond to the drug (nivolumab, pembrolizumab or atezolizumab), that’s a good sign. This avenue of investigation may also help researchers figure out why some patients do not benefit from checkpoint inhibitor drugs, and how to combine those drugs with other treatments to increase response rates.

While looking for activated immune cells in the blood is not yet predictive enough for routine clinical use, such tests could provide timely information. Monitoring the immune response could potentially help oncologists and patients decide, within just a few weeks of starting immunotherapy drugs, whether to continue with the treatment or combine it with something else, says co-senior author Suresh Ramalingam, MD, Winship’s deputy director.

“We hypothesize that re-activated CD8 T cells first proliferate in the lymph nodes, then transition through the blood and migrate to the inflamed tissue,” says Rafi Ahmed, PhD, director of the Vaccine Center and a Georgia Research Alliance Eminent Scholar. “We believe some of the activated T cells in patients’ blood may be on their way to the tumor.”

The rest of the Emory Vaccine Center/Winship Cancer Institute press release is here. A few additional points:

*An early increase in PD-1+ CD8 T cells appears important. Having a CD8 T cell response after four weeks or a mostly PD-1-negative response was an indicator against clinical benefit– please see pie chart below or the PNAS paper (main and supplemental) for outcome details. All patients with partial responses survived at least one year, while just one with progressive disease survived one year after treatment initiation. Survival data was not available for three patients with progressive disease.

*Researchers probed for T cells specific for Epstein-Barr virus, which many people are exposed to in childhood. Their numbers did not increase when patients were given PD-1-targeting drugs, suggesting that the ensuing immune response is enriched for tumor-specific T cells. From the paper: “There are no known antigens specific to non-small cell lung cancer, and several reports now suggest that immunotherapies may rescue CD8 T cells recognizing mutation-derived neoantigens unique to each patient.”

*Similar findings from Penn with melanoma patients were published in April in Nature.

*The Emory/Winship study began before the FDA approval of pembrolizumab last fall as a first-line treatment for non-small cell lung cancer. Most of the patients described in the PNAS paper had already received chemotherapy and/or radiation before immunotherapy.

*A test of PD-L1 levels, obtained via biopsy, is now used to decide whether to initiate immunotherapy drugs in lung cancer. The test can be interpreted as a measure of whether the tumor site is inflamed at baseline, which may be complementary to information from the blood about the immune response.

*Recent radiation treatment seemed to elevate baseline CD8 T cell levels for two patients in the PNAS paper. That’s significant when trying to figure out how to combine radiation with immunotherapy. Winship investigators are using the information obtained from this study to guide the design of studies following radiation with immunotherapy for small cell lung cancer.

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Posted on by Quinn Eastman in Cancer, Immunology Leave a comment

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Quinn Eastman

Science Writer, Research Communications qeastma@emory.edu 404-727-7829 Office

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