Background/Purpose:

Background: The recent discovery of the immune checkpoint blockade that targets the regulatory pathways in T cells to enhance antitumor immune responses has led to major advances in the strategy of cancer care. However, the occurrence of serious immune-related adverse events (irAEs) in the treated patients has been increasingly reported in the literature suggesting an aberrant autoimmune T cell activation.  We conducted a systematic review of case reports documenting the development of irAEs in cancer patients following treatment with anti-cytotoxic T lymphocyte antigen (CTLA-4) or anti-programmed cell death 1 (PD-1), to identify the type of cancer, and the clinical scenario of the irAEs reported in these cases.

Methods: We searched Medline, EMBASE, Web of Science, PubMed ePubs, and Cochrane CENTRAL with no language restriction from inception through April 2015. We included case reports describing the occurrence of irAEs in cancer patients after being treated with anti CTLA-4 or anti PD-1/PD-L1 antibodies. Bibliography search of the included citations was also performed. We extracted data on the type of cancer, the type of immune checkpoint blockade, the nature of the irAEs and their reported outcome.

Results: Out of 2,109 unique citations identified, 152 publications met our inclusion criteria, reporting on 197 case reports. More than half of the reported cases were from the United States (56.4%). The mean age of the cases was 60.2 years (standard deviation, 12.3 years). One hundred and twenty three patients (62.4%) were male. Metastatic melanoma was reported in the majority of the cases (95.4%). Patients with metastatic prostatic cancer, lung cancer, and bladder cancer were seen in 3.0%, 1.0%, and 0.5% respectively. Patients were categorized according to the type of the immune checkpoint blockade. One hundred and eighty six patients (94.4%) were treated with anti CTLA-4 antibodies, either ipilimumab or tremelimumab. While only 11 patients (5.6%) were treated with anti PD-1 antibodies, either nivolumab or pembrolizumab. Frequency of adverse events are shown in the table. Complete resolution of the adverse events was observed in the majority of cases regardless of the type of the immune checkpoint blockade. However, persistent symptoms was reported in 13.7% of the reported cases. Death from complicated irAEs was seen in 4.1%, all of them reported in patients treated with ipilimumab.

Conclusion: Systematic reviews can help identify rare adverse events. Our findings suggest that following treatment with immune checkpoint blockade, irAEs are common. Further longitudinal studies should be conducted to better identify the incidence and quantify the risk of irAEs after treatment with these novel agents.