Treatment for clear cell renal cell carcinoma (ccRCC) often includes immunotherapy. However, it does not always work and there is no way to predict whether it will be effective for a patient. Now, researchers at the Francis Crick Institute, the Royal Marsden NHS Foundation Trust, and UCL have found immune cell patterns within tumors that can help predict if patients with kidney cancer will respond to immunotherapy.

Their findings are published in the journal Cancer Cell in a paper titled, “Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma.”

The researchers analyzed 115 tumor samples from 15 people with metastatic ccRCC who received the immunotherapy drug nivolumab through the ADAPTeR clinical trial.

“ADAPTeR is a prospective, Phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic ccRCC aiming to understand the mechanism underpinning therapeutic response,” the researchers wrote. “Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response.”

“Analyzing multiple samples from each patient, both from different parts of the kidney tumor and from tumors that have spread to other organs, is critically important. It’s known that molecular information in kidney cancer is distributed like a mosaic within the tumor— such that taking a single sample may not capture all the information needed for a comprehensive analysis,” explained Lewis Au, FRACP, co-lead author, oncologist, and research fellow in the Cancer Dynamics Laboratory at the Crick.

The researchers took tumor samples at various stages of cancer treatment. The researchers observed different tumor characteristics and measures of immune response to see if any corresponded to immunotherapy.

They discovered an increased number of specific “clonal” T-cell receptors, proteins on the surface of T cells present in the tumor before treatment, was linked to a greater chance of positive immunotherapy response. And if these T-cell receptors were maintained during treatment, this was the strongest indicator that treatment would be effective.

Lewis added: “In people who respond to this immunotherapy there is a group of T cells which appear to have already recognized the tumor, through these specific receptors. These cells, with potential tumor killing activity, are sitting on the tumor but they need the drug to kick them into action. When T cells bearing these receptors are effectively attacking the tumor, we can see them accumulating within the cancer. But in cases where their receptors don’t recognize the tumor, they are replaced by other T cells with different receptors as the immune system tries to find a match that recognizes and kills the tumor.

“Our study also shows how in-depth studies of cancer biology within clinical trials can be incredibly powerful.”

Emine Hatipoglu, co-lead author, specialist oncology registrar, and Cancer Research UK clinical research fellow at UCL Cancer Institute added: “This study helps us understand why this immunotherapy sometimes works and sometimes doesn’t. There is a specific T-cell response that increases the chance of effective treatment. With this deeper biological knowledge, it might be possible to find new cellular or combination therapies that increase the chance of survival for our patients.”

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