Targeting CTLA ‐4 in cancer: Is it the ideal companion for PD ‐1 blockade immunotherapy combinations?

Abstract Immunotherapy approaches boosting spontaneous and durable antitumor immune responses through immune checkpoint blockade are revolutionizing treatment and patient outcomes in solid tumors and hematological malignancies. Among the various inhibitory molecules employed by the immune system to regulate the adaptive immune responses, cytotoxic T lymphocyte antigen‐4 (CTLA‐4) is the first successfully targeted immune checkpoint molecule in the clinic, giving rise to significant but selective benefit either when targeted alone or in combination with anti‐programmed cell death protein‐1 (PD‐1) antibodies (Abs). However, the use of anti‐CTLA‐4 Abs was associated with the incidence of autoimmune‐like adverse events (AEs), which were particularly frequent and severe with the use of combinational strategies. Nevertheless, the higher incidence of AEs is associated with an improved clinical benefit indicating treatment response. A prompt recognition of AEs followed by early and adequate treatment with immunosuppressive agents allows the management of these potentially serious AEs. This narrative review aims to summarize CTLA‐4 biology, the rationale for the use as a companion for anti‐PD‐1 Abs in humans with results from the most relevant Phase III clinical trials including anti‐CTLA‐4 Abs in combination with anti‐PD‐1 Abs in solid tumors.