Cancer Immunotherapy Side Effect Risk Linked to Genetics

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

The discovery, published online today in the journal Natural medicine, was carried out with a mathematical model that allowed the researchers to take an extraordinary analytical leap: using data on cancer-related mutations in tumor tissue, the researchers were able to infer characteristics of the genetic inheritance of the patients. They found that patients with specific germline variants (common inherited alterations in genes) were more likely to develop autoimmune-like side effects of checkpoint inhibitor treatment.

By identifying these patients before treatment, using modeling and tumor profiling technology already available at many US cancer centers, clinicians can modify therapy to minimize side effects, the study authors say.

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

“Efforts to identify patients at high risk of toxicity have largely focused on the genetics of tumor tissue. Our hypothesis in this study was that patient germline genetics influence the risk of developing these toxicities.” “.

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

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

To see if the patients’ germline DNA, the genetic material inside their cells, contains clues to their susceptibility to such events, the researchers conducted a genome-wide association study (GWAS) of 1715 patients treated with checkpoint inhibitors in 12 cancer types. GWAS analyze the genome to see if sections that often vary from person to person are associated with a particular disease.

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

As part of the Dana-Farber Profile program, tumor tissue from the 1,715 study patients was analyzed 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 which uses raw data from Profile to generate reads of patients’ genomes and to identify any variations within them.

“We went from 500 genes that were targeted in the tumor to now common genome-wide variations in this group of patients,” says Gusev.

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

“In our initial cohort of patients, we found that the rate of checkpoint inhibitor-related toxicities was three times higher in patients who had a genomic alteration close to IL7,” says study co-senior author Toni Choueiri, MD, from Dana-Farber. “In the other two groups of patients, the rate of toxicity 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 a co-senior author of the study. The researchers found that patients harboring the IL7 germline variant had increased lymphocyte stability during and after treatment with checkpoint inhibitors. , and that this stability was related to a higher risk of adverse events and better survival.

It makes biological sense that stable, vigorous lymphocytes could be responsible for both autoimmune side effects and a more vicious 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 the immune-related side effects of checkpoint inhibitor therapy. Ultimately, the finding may help oncologists further personalize treatment for patients: those likely to experience severe side effects may be recommended less intense or shorter treatment courses, while those at low risk of toxicity they may benefit from higher doses or more aggressive treatment, the study authors say.

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

Citation: Risk of Side Effects of Cancer Immunotherapy Linked to Genetics (December 16, 2022) Accessed December 16, 2022 at https://medicalxpress.com/news/2022-12-side-effects-cancer- immunotherapy-linked.html

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