Risk of side effects from cancer immunotherapy linked to genetics

Risk of side effects from cancer immunotherapy linked to genetics

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Although they have revolutionized cancer treatment, drugs known as immune checkpoint inhibitors can produce a range of adverse immune system-related side effects. In a new study, scientists at the Dana-Farber Cancer Institute identify, for the first time, inherited genetic variations that put patients at high risk for these complications.

The discovery, reported online today in the newspaper natural medicine, was carried out with a mathematical model that allowed researchers to make an extraordinary analytical leap: using data on cancer-related mutations in tumor tissues, researchers were able to infer the characteristics of patients’ genetic inheritance. They found that patients with specific germline variants – common inherited alterations in genes – had an increased likelihood of developing autoimmune-like side effects as a result of checkpoint inhibitor treatment.

By identifying these patients before treatment — using the tumor profiling model and technology already available at many U.S. cancer centers — doctors may be able to modify treatment to minimize side effects, the authors say. study.

“Immune checkpoint inhibitors are remarkably effective in a variety of cancer types, but patients often suffer from immune system-related toxicities, some of which can be quite severe,” says co-lead author Alexander Gusev, Ph. D., of Dana-Farber, the Broad Institute of MIT and Harvard, and Brigham and Women’s Hospital.

“Efforts to identify patients at high risk for toxicity 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.”

About 20% of patients treated with checkpoint inhibitors develop moderate to severe side effects, a figure that is consistent with all types of cancer for which the drugs are approved. Side effects mirror those associated with autoimmune diseases: skin problems, fatigue, joint pain, recurring fever, colitis and, in severe cases, myocarditis, inflammation of the heart muscle.

These symptoms are the result of an overly aggressive attack by the immune system. Checkpoint inhibitors work by lowering the barriers to an immune system attack on cancer cells, but because normal cells display some of the same barriers, they can also be attacked.

To see if patients’ germline DNA – the genetic material of their cells – contains clues to their susceptibility to such events, the researchers conducted a genome-wide association study (GWAS) of 1,715 patients. treated with checkpoint inhibitors in 12 types of cancer. GWAS scan the genome to see if sections that often vary from person to person are associated with a particular disease.

Normally, this involves technology that reads each letter of DNA, in order, in a patient’s normal cells (often blood cells). For the new study, however, Gusev and his colleagues devised a way to do a GWAS study with data already available from genomic analysis of patients’ tumor tissue.

Under Dana-Farber’s Profile program, the 1,715 patients in the study had their tumor tissue scanned for mutations in about 500 cancer-related genes. While this helped identify genetic vulnerabilities within these tumors, it did not exhaust the genomic data collected for each one. Gusev created a mathematical model that uses the raw data from Profile to generate reads of patients’ genomes and to identify any variation within them.

“We’ve gone from having 500 tumor-targeted genes to now common genome-wide variations in this group of patients,” Gusev notes.

With the genomic data in hand, the researchers analyzed patients’ medical records to see if those who experienced moderate to severe side effects from checkpoint inhibitors carried common genomic variations. They found a link with three of these variations, the most important of which was close to the IL7 gene. They then confirmed these results in a group of 196 patients treated at Massachusetts General Hospital and in 2,275 patients who participated in clinical trials of atezolizumab, a checkpoint inhibitor.

“In our initial cohort of patients, we found that the rate of checkpoint inhibitor-related toxicities was three times higher in patients with genomic alterations close to IL7,” says the co-lead author of the paper. study, Toni Choueiri, MD, of Dana-Farber. “In the other two patient groups, the toxicity rate was five times higher in the IL7 group.”

“The IL7 gene is known to help stabilize lymphocytes [white blood cells that help fight disease]notes Matthew Freedman, MD, of Dana-Farber, also co-lead author of the study. The researchers found that patients with the IL7 germline variant had greater lymphocyte stability during and after the checkpoint inhibitor treatment, and that this stability was linked to a higher risk of adverse events and improved survival.

It makes biological sense that stable, vigorous lymphocytes could be responsible for both autoimmune-like side effects and a fiercer attack on tumors, prolonging patient survival, the researchers say.

The study provides the first evidence that inherited genetic variations may be a marker of increased susceptibility to immune system-related side effects of checkpoint inhibitor treatment. The discovery may ultimately help oncologists further personalize treatment for patients: those who are likely to experience severe side effects may be recommended for less intense or shorter treatments, while those at low risk of toxicity may benefit from higher doses. elevated or more aggressive treatment, say the study authors.

More information:
Groha, S. et al, Germline variants associated with immune checkpoint blockade toxicity, natural medicine (2022). DOI: 10.1038/s41591-022-02094-6

Provided by the Dana-Farber Cancer Institute

Quote: Risk of Side Effects of Cancer Immunotherapy Genetically Linked (December 16, 2022) Retrieved December 16, 2022 from https://medicalxpress.com/news/2022-12-side-effects-cancer-immunotherapy-linked. html

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