Encephalitis—A Rare Toxicity of Immunotherapy Treatment

Rare But Serious Side Effects Linked to Immune Checkpoint Inhibitors

After a patient with cancer who was receiving immunotherapy developed encephalitis and died 18 months into treatment, researchers at Vanderbilt-Ingram Cancer Center (VICC) investigated why the complication had occurred.

After performing a molecular analysis of the disease’s pathology, and examining data to determine the incidence of similar occurrences, the investigators found T cells known to react to Epstein-Barr virus in the affected tissue of the patient. They also noted one highly prevalent but uncharacterized T-cell population that appeared similar to the Epstein-Barr virus-specific T cells.

In addition, the researchers conducted a data review that identified 22 cases of meningoencephalitis in 2,501 patients treated with immune checkpoint inhibitors at four large academic medical centers, although it is not known whether this virus was a factor in those cases.

The results, published July 22 in Nature Medicine, are the latest findings by VICC researchers chronicling rare but serious toxicities that can occur with immune checkpoint inhibitors, the most widely prescribed class of immunotherapies.

The study authors emphasize that while such reports are not intended to alarm the public, as they are uncommon, they are nonetheless significant because such drugs are being employed more frequently in an increasing number of cancer types. And, “the more patients we use them in, the more that fraction as an absolute number of patients affected becomes larger,” say the authors.

The researchers are trying to understand what triggers these adverse reactions to immune checkpoint inhibitors and are searching for biomarkers that could indicate which patients are most susceptible. They confess that, at this point, it remains a complete mystery.

The analysis of tissue from the Vanderbilt patient identified Epstein-Barr-virus-specific T cell receptors and Epstein-Barr-positive lymphocytes. The report is believed to be the first one published of a molecular analysis of a neurotoxicity caused by checkpoint inhibitors, the first evidence linking a viral infection to an adverse event from this drug class, and the first detailed identification and phenotyping of culprit immune-cell populations.

The molecular analysis revealed something unexpected regarding the patient’s immune response: there was a higher frequency of CD4 positive T cells (usually considered as playing a helper role in immune responses) with a “killer” profile than CD8 positive T cells, which are typically the “killer” cells.

The study authors acknowledge that the role of the CD4 positive T cells with immune-related adverse events merits further study.

Source: Vanderbilt University, July 22, 2019