The Severe Immunotherapy Complications (SIC) Service and Clinical-Translational Research Effort at Mass General Cancer Center is working to address the urgent need to understand how and why immune-related adverse events (irAEs) occur. SIC's multidisciplinary team comprises more than 50 individuals across 19 areas of the hospital, and this unique group of clinicians and researchers are involved in the care of every patient admitted with a suspected irAE after checkpoint blockade immunotherapy.

In this interview series, Kerry Reynolds, MD, director of the SIC service, sits down with a SIC team member for a deeper-dive into their work. This month we meet Leeann Burton, MD, a neuromuscular neurologist at Massachusetts General Hospital who specializes in patients with neurological immune-related adverse events.

Kerry Reynolds, MD
Kerry Reynolds, MD

Kerry: Leeann, thank you so much for joining us today. We really enjoyed the most recent talk that you gave during the Severe Immunotherapy Complications Service seminar series. You mapped out a framework to think through immune checkpoint inhibitor (ICI)-induced encephalitis versus tumor progression versus pseudoprogression. Can you tell us more about it?

Leeann: Absolutely, and thanks so much for inviting me today. For the seminar series presentation, I wanted to highlight some of the challenges in diagnosing ICI-induced encephalitis in cancer patients. ICI-induced encephalitis is rare but treatable, so it’s important for providers to recognize. However, it can manifest with non-specific symptoms such as confusion, cognitive difficulties, and impaired consciousness, for which there are many other possible causes. In patients with brain tumors, the differential diagnosis also includes tumor progression and tumor pseudoprogression, which has been reported with ICI treatment. Because ICI-induced encephalitis, tumor progression, and tumor pseudoprogression can all cause brain inflammation, they show similar abnormalities on diagnostic tests like MRI, lumbar puncture, and EEG. The overlap can make it difficult to differentiate between these possibilities, but there are characteristic clinical features of each that can help. We developed a framework to delineate which symptoms, exam findings, and test abnormalities would make ICI-induced encephalitis, tumor progression, or tumor pseudoprogression more or less likely. The goal is to help providers assimilate available clinical information to weigh these different possibilities and make an accurate diagnosis.

Leeann Burton, MD
Leeann Burton, MD

Kerry: How do you think this work informs the field moving forward, or what should individuals consider when trying to decide if an event is truly “immune-mediated”?

Leeann: Diagnosing a neurologic immune-mediated adverse event requires looking at the full clinical picture. We don’t have a single test that can tell us if a patient’s syndrome is truly related to ICI therapy. In addition to information gleaned from diagnostic tests, critical pieces of information include the timing of symptom onset and the presence of non-neurologic immune-related adverse events, which can increase the likelihood that neurologic symptoms are ICI-related. We’ve recently published neurologic immune-related adverse events disease definitions, which I think is the first step towards accurately diagnosing these conditions. However, there’s still a lot of uncertainty, particularly in patients who have other possible causes of neurologic symptoms. We’ve incorporated uncertainty into the disease definitions by defining criteria for definite, probable, and possible diagnoses. As our knowledge of neurologic immune-mediated adverse events grows and biomarkers are developed, my hope is that more patients will meet criteria for definite diagnosis. But until that happens, we need to rely on the information we have to treat patients. By creating this framework for evaluating ICI-related encephalitis in patients with brain tumors, our goal was to flesh out one of the “gray areas” to help providers manage these challenging cases.

Kerry: You recently received the Young Investigator Research Grant from the Dysimmune Diseases Foundation. What is the most pressing need, in your opinion, in the field of neuro immune-related adverse events? In short, where do we go from here?

Leeann: A major unanswered question in the field is what the mechanisms are that trigger and sustain immune-related adverse events. Understanding these pathways is critical for us to optimally predict risk, diagnose, and treat patients. Currently, we treat neurologic immune-related adverse events with blanket immunosuppression, which has side effects and may reduce the anti-tumor efficacy of ICIs. If we can identify the specific immune pathways that are disrupted, we can use therapies that target them specifically. I think this is the best strategy to limit the toxicities of ICIs while preserving their lifesaving anti-cancer benefits. With the support of the Dysimmune Diseases Foundation, I will be collaborating with the SIC team and Dr. Chloe Villani’s translational biology lab to apply cutting-edge single-cell RNA sequencing analytic strategies to study the pathogenic mechanisms underlying neuromuscular immune-related adverse events. I am thrilled that the Dysimmune Diseases Foundation is helping to fund this important work.

Kerry: We know you trained closely with Dr. Amanda Guidon who we will be interviewing next month. What was that training program like and what made it a success?

Leeann: I have been extremely fortunate to train with physicians who are so dedicated to providing excellent care to their patients, advancing their fields through research, and fostering the development of trainees. I completed the Harvard Neuromuscular Medicine Fellowship last year, which Dr. Amanda Guidon directs. This is a rigorous 1-year program that I think is so successful due to the richness and breadth of the clinical experience and the commitment of the faculty. I have really valued the teaching, encouragement, and mentorship from the neuromuscular staff at both MGH and BWH. Dr. Guidon’s mentorship in particular has been instrumental in helping me articulate and advance my career goals.


Guidon AC, Burton LB, Chwalisz BK, Hillis J, Schaller TH, Amato AA, Betof Warner A, Brastianos PK, Cho TA, Clardy SL, Cohen JV, Dietrich J, Dougan M, Doughty CT, Dubey D, Gelfand JM, Guptill JT, Johnson DB, Juel VC, Kadish R, Kolb N, LeBoeuf NR, Linnoila J, Mammen AL, Martinez-Lage M, Mooradian MJ, Naidoo J, Neilan TG, Reardon DA, Rubin KM, Santomasso BD, Sullivan RJ, Wang N, Woodman K, Zubiri L, Louv WC, Reynolds KL. Consensus disease definitions for neurologic immune-related adverse events of immune checkpoint inhibitors. J Immunother Cancer. 2021 Jul;9(7):e002890. doi: 10.1136/jitc-2021-002890.