The mechanisms governing immune-related adverse events resulting from checkpoint inhibition therapy for cancer remain a mystery to rheumatologists and oncologists alike, according to a presenter at the Biologic Therapies Summit.
"The problem with irAEs, which oncologists are now recognizing, is that around 60% of patients, or higher, will develop grade 3 or higher events," Noha Abdel-Wahab, MD, PhD, assistant professor in the department of rheumatology and clinical immunology at the University of Texas MD Anderson Cancer Center, told attendees.
These events will interfere with cancer outcomes, require immunosuppression and can result in long-term toxicity, according to Abdel-Wahab.
"Some are fatal, and up to 39% may require discontinuation of cancer therapy," she said.
Meanwhile, investigation into biomarkers such as CD4 and CD8 T cells, white blood cells, eosinophil count, lymphocyte or monocyte count, and interleukins (ILs) has not provided adequate answers into the underlying mechanism of irAEs, according to Abdel-Wahab.
Further investigation has targeted C-reactive protein, GMCSF and a various of markers in the HLA family, including HLA-B27 and HLA-DR4, with similar results.
"Biomarker discovery is rapidly advancing, but signatures remain heterogeneous, highlighting the need for standardized approaches," Abdel-Wahab said.
With so many questions surrounding the mechanisms, it follows that researchers and clinicians have so far failed to define the optimal type, dose and duration of immunosuppressive medication required to manage irAEs, she added. It is also unknown whether the efficacy of these medications is impacted by the type of event, what other events may occur and how all of these factors impact cancer treatment.
Despite these obstacles, rheumatologists are tasked with managing these patients in the clinic every day.
"Managing irAEs requires a balance between managing symptoms and maintaining anti-tumor activity," Abdel-Wahab said.
However, reaching this balance has proven challenging, given that irAEs in the neurological, cardiac, renal, hepatic, pulmonary, cutaneous, gastrointestinal and musculoskeletal systems have all been reported, she added.
"Using a one-size approach is likely inappropriate," Abdel-Wahab said.
Corticosteroids have been used to manage these events, but data describing timing, duration and dosing have yet to provide clear answers, according to Abdel-Wahab. Early initiation of steroids may be beneficial, while peak, rather than cumulative, corticosteroid dose may have the most impact in managing irAEs. However, further study is needed to adequately define the protocols, Abdel-Wahab said.
Similarly, TNF, IL-6/Th-17 and Janus kinase inhibition have all been tested, with few conclusions reached by either clinicians or researchers.
"There is a need for personalized, informed strategies to develop approaches to manage the toxicity," Abdel-Wahab said. "At this point, we are just managing symptoms. We have no insight on the immune mechanisms."