Preserving the CTLA-4 Checkpoint for Safer and More Effective Cancer Immunotherapy

Cancer therapeutic effect (CITE) of anti-CTLA-4 antibodies is due to selective depletion of tumor-infiltrating regulatory T cells (Treg). Immunotherapy-related adverse events (irAE) is attributable to CTLA-4 inactivation. pH-insensitive antibodies direct CTLA-4 to lysosomal degradation. pH-sensitive anti-CTLA-4 antibodies minimize irAE by preserving CTLA-4 recycling. Preserving CTLA-4 recycling enhances selective depletion of tumor-infiltrating Treg. Preserving the CTLA-4 checkpoint allows safer and more effective immunotherapy. A major paradigm in cancer immunotherapy is the use of checkpoint inhibitors to break regulatory mechanisms that usually guard the host against autoimmune diseases. CTLA-4-targeting immunotherapy was the first example that helped establish this paradigm. However, the clinically tested anti-CTLA-4 antibodies exhibit suboptimal efficacy but high toxicity. Recent studies have demonstrated that immunotherapy-related adverse events (irAE) and the cancer immunotherapeutic effect (CITE) represent distinct and therapeutically separable activities of anti-CTLA-4 antibodies. The former is attributable to inactivation of the CTLA-4 checkpoint, while the latter is due to selective depletion of regulatory T cells (Treg) in a tumor microenvironment. Here we argue that for safer and more effective CTLA-4-targeting immune therapy, one should preserve rather than inhibit the CTLA-4 checkpoint while enhancing the efficacy and selectivity of Treg depletion in a tumor microenvironment. A major paradigm in cancer immunotherapy is the use of checkpoint inhibitors to break regulatory mechanisms that usually guard the host against autoimmune diseases. CTLA-4-targeting immunotherapy was the first example that helped establish this paradigm. However, the clinically tested anti-CTLA-4 antibodies exhibit suboptimal efficacy but high toxicity. Recent studies have demonstrated that immunotherapy-related adverse events (irAE) and the cancer immunotherapeutic effect (CITE) represent distinct and therapeutically separable activities of anti-CTLA-4 antibodies. The former is attributable to inactivation of the CTLA-4 checkpoint, while the latter is due to selective depletion of regulatory T cells (Treg) in a tumor microenvironment. Here we argue that for safer and more effective CTLA-4-targeting immune therapy, one should preserve rather than inhibit the CTLA-4 checkpoint while enhancing the efficacy and selectivity of Treg depletion in a tumor microenvironment. cancer treatments for patients administrated after surgery. the process that leads to increased frequency of T or B cells with a unique antigen receptor. the major cell types that present antigens to activate T cells. a fragment of immunoglobulin that mediates binding to an antigen. a crystallizable fragment of immunoglobulin. cancer treatments for patients administrated before surgery. cellular receptor-mediated uptake and internalization of ligand on another cell. the normal cells, molecules, and blood vessels that surround and feed a tumor cell.