Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma

In a comparison of tumors from patients with melanoma who benefitted from blockade of cytotoxic T-lymphocyte antigen 4 (CTLA-4) with tumors from patients who did not benefit, tumor neoantigens were detected that were strongly associated with a response. Immune checkpoint blockade has led to durable antitumor effects in patients with metastatic melanoma, non–small-cell lung cancer, and other tumor types, but the factors determining whether a patient will have a response remain elusive. 1 , 2 The fully human monoclonal antibodies ipilimumab and tremelimumab block cytotoxic T-lymphocyte antigen 4 (CTLA-4), resulting in T-cell activation. Some studies have established correlations between outcomes with ipilimumab and peripheral-blood lymphocyte count, markers of T-cell activation, 3 an “inflammatory” microenvironment, 4 , 5 and maintenance of high-frequency T-cell receptor clonotypes. 6 The relationship among the genomic landscape of the tumor, the mutational load, and the benefit from treatment remains obscure. . . .