Even as they’ve revolutionized cancer treatment, immune checkpoint inhibitors have been shown to produce a range of adverse immune-related side effects. Researchers have now identified inherited genetic variations that may place patients at high risk for complications when undergoing treatment with immune checkpoint inhibitors, according to a novel study published by Groha et al in Nature Medicine.
Background
Using data about cancer-related mutations in tumor tissue, researchers were able to infer features of patients’ genetic inheritance and found that patients with specific germline variants had an increased likelihood of developing autoimmune-like side effects from immune checkpoint inhibitor treatment. By identifying which patients may be at higher risk for adverse side effects prior to treatment—using the model and tumor-profiling technology already available at many U.S. cancer centers—clinicians may be able to modify therapy to minimize these side effects.
“Immune checkpoint inhibitors are remarkably effective across a variety of cancer types, but patients often experience immune-related toxicities, some of which can be quite severe,” explained co–senior author Alexander Gusev, PhD, Associate Professor of Medicine at Harvard Medical School and in the Department of Medical Oncology at Dana-Farber Cancer Institute. “Efforts to identify patients at high risk for toxicities have largely focused on genetic aspects of tumor tissue. Our hypothesis in this study was that the germline genetics of the patient influence the risk of developing these toxicities.”
Roughly 20% of patients treated with immune checkpoint inhibitors may develop moderate to severe side effects—a figure consistent across all cancer types—as the result of an overaggressive immune system. The side effects mirror those associated with autoimmune diseases and include skin problems, fatigue, joint pain, recurring fever, colitis, and myocarditis in severe cases.
Study Methods and Results
To evaluate whether patients’ germline DNA may hold clues about their susceptibility to such events, researchers conducted a genome-wide association study of 1,715 patients undergoing immune checkpoint inhibitor treatment across 12 cancer types. Though genome-wide analysis studies typically sample sections of the genome to compare disease association between individuals by using technology to sequentially read each letter of DNA, for the new study, Dr. Gusev and his colleagues devised a way to conduct the evaluation with data already on hand from a previous genomic analysis of the patients’ tumor tissue.
As part of the Profile program at Dana-Farber, the 1,715 patients involved in the study had received tumor tissue scans to search for mutations in about 500 genes linked to cancer. While this helped identify genetic vulnerabilities within these tumors, the scans didn’t exhaust the genomic data collected for each patient. Dr. Gusev created a mathematic model that used raw data from the Profile program to generate readouts of the patients’ genomes—and to identify any variations within them.
“We went from 500 genes that were targeted in the tumor to, now, common variations genome-wide in this group of patients,” Dr. Gusev noted.
The researchers used the genomic data to analyze the patients’ medical records to see if those who experienced moderate to severe side effects from the immune checkpoint inhibitors carried any common genomic variations. They found a connection to three such variations, the most prominent of which was near the IL7 gene. The researchers then confirmed these findings in a group of 196 patients and in a separate group of 2,275 patients who took part in clinical trials of the immune checkpoint inhibitor atezolizumab.
“In our initial cohort of patients, we found that the rate of [immune] checkpoint inhibitor–related toxicities was three times higher in patients who had a genomic alteration near gene IL7," detailed study co–senior author Toni Choueiri, MD, the Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School, as well as Director of the Lank Center for Genitourinary Oncology and Medical Director of International Strategic Initiatives at the Dana-Farber Cancer Institute. "In the two other groups of patients, the toxicity rate was five time[s] higher in the IL7 [gene] group.”
Conclusions
“The IL7 gene is known to help stabilize lymphocytes,” noted co–senior study author Matthew Freedman, MD, Professor of Medicine at Harvard Medical School and a researcher in the Department of Medical Oncology at Dana-Farber Cancer Institute. The researchers concluded that patients harboring the IL7 germline variant had greater lymphocyte stability during and after immune checkpoint inhibitor treatment, and that this stability was linked to a higher risk of adverse events and improved survival. They noted that stable, vigorous lymphocytes may be responsible both for autoimmune-like side effects and a fiercer attack on tumors—which may extend patient survival.
The study provided the first evidence that inherited genetic variations can be a marker for increased susceptibility to immune-related side effects from immune checkpoint inhibitor therapy. The findings may ultimately help oncologists further personalize treatment for patients; those found likely to experience harsh side effects may be recommended for less intense or shorter courses of treatment, whereas those at low risk for toxicity may benefit from higher doses or more aggressive treatment.
Disclosure: The research in this study was supported by the National Institutes of Health; the Claudia Adams Barr Foundation; the Louis B. Mayer Foundation; the Doris Duke Charitable Foundation; a Dana-Farber Trustee Fellowship; the Dana- Farber/Harvard Cancer Center Kidney SPORE and Program; the Kohlberg Chair at Harvard Medical School; as well as the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at Dana-Farber. For full disclosures of the study authors, visit nature.com.
