Immunotherapy Service Aims to Address and Study Immune-Related Toxicities

Kerry L. Reynolds, MD

Massachusetts General Hospital (Mass Gen) in Boston established its immunotherapy toxicity service care team in part because of the experience of David M., a patient treated there for metastatic melanoma that spread to the lung and brain.

Kerry L. Reynolds, MD, director of the Severe Immunotherapy Complications Service at Mass Gen, said David received 2 doses of an anti—CTLA-4 and a PD-1-inhibitor. Shortly after that second dose, he presented at Mass Gen with coughing, shortness of breath, and an oxygen saturation of 48%. He was treated for immune checkpoint-related pneumonitis and left the hospital 5 days later apparently on the road to recovery.

Four weeks later, he was readmitted due to diffuse diarrhea, and he was profoundly immunosuppressed from the steroids he was taking to treat the pneumonitis. A colonoscopy showed he had a lymphocytic/histiocytic infiltrate consistent with immune checkpoint colitis. 

Reynolds said physicians tried everything they could think of to treat him. Despite their best efforts, David died in June 2016.

“A couple of days before, when he realized he wasn't going to make it, he looked up at our team and said, ‘You have to share this case and you have to learn from this,’” she said. “We promised him then that we would.”

A few days later, an autopsy showed there was no evidence of melanoma in his body.

“His disease was eradicated,” Reynolds said. “But he died from overwhelming toxicity and immunosuppression.”

Reynolds told her audience at the 18th International Kidney Cancer Symposium that David’s case forced physicians at Mass Gen to consider how to prepare doctors to handle immune-related adverse events (IRAEs) and create best practices for managing these incidents.

She noted that the SEER database includes more than 271,000 patients currently eligible for immunotherapy. That number does not include patients with early stage disease who receive immune checkpoint inhibitors for recurrence, those already on treatment, or patients enrolled into 1 of more than 240 combination trials.

“It is easy to say we will be treating more than 500,000 patients in the next year,” Reynolds said. “So, when my colleagues talk about myocarditis at 1% or severe neurological toxicity at 1%, we’re talking about 5000 patients each time.”

To address the questions surrounding IRAEs, Mass Gen’s Severe Immunotherapy Complications service brings together 48 experts across 19 departments incorporating all the diseases treatable with immunotherapy agents. The service includes translational and clinical investigation to both improve treatment today and to develop better treatments in the future.

Members meet in a biweekly case conference call to review each incidence of toxicity. The members review each patient and the relevant literature, and look for gaps in their knowledge. Then, to fill those gaps, Mass Gen has established a registry of patients treated at the hospital with immune checkpoint inhibitors.

The service is already paying off. Reynolds detailed the case of a 73 year-old man being treated with axitinib (Inlyta) for renal cell carcinoma. Before beginning his second round of treatment, he complained of fatigue, cough, and chest constriction.

At the start of his third cycle, he was admitted to the hospital because his heart rate was above 150 and his troponin level was highly elevated.

Reynolds said the case was complicated because the patient had risk factors for regular coronary artery disease, such as hypertension and chronic kidney disease, but he was also at risk for myocarditis. The service determined a biopsy was the best way to proceed, the results of which showed lymphocytic infiltration. The patient was started on high dose steroids later that day.

There have been successes reported in the laboratory, too. Investigators working in the laboratory of Alexandra-Chloe Villani, PhD, have found that IRAEs are not patient-specific, but rather, shared biological programs drive these events. Furthermore, IRAEs are more closely related to the immune system than the tumor.