Abstract Patient immune response to tumor can drive profound and durable clinical benefit, but the contribution of antibodies to this benefit is poorly understood. To further our understanding of the role of the humoral response, we compared antibody sequence repertoires of durable responder and non-responder melanoma patients before and during checkpoint inhibitor treatment. We collected pre- and on-treatment peripheral blood from 26 melanoma patients treated with pembrolizumab (9), ipilimumab (8) or nivolumab+ipilimumab (9). Of the 26 patients, 14 were durable responders (RECIST stable disease, partial response, or complete response for at least 6 months) and 12 were non-responders. We generated natively paired heavy and light chain antibody sequences from individual IgG plasmablasts (CD19+CD20-CD38+CD3-CD14-IgA-IgM-IgD-). Sequences were obtained from a total of 26,725 plasmablasts. These sequences were used to reconstruct lineages (sets of plasmablasts likely derived from a common progenitor B cell) where each lineage shares heavy and light V genes, CDR3 length and 80% sequence similarity in CDR3s. Durable responders exhibited an increase in somatic hypermutation (SHM) after initiation of treatment. In contrast, no significant change in SHM was observed in non-responders. Higher SHM was also observed in on-treatment repertoires of responders compared with those of non-responders suggesting that T cell checkpoint inhibitors promote activation of humoral immunity in clinical responders. Furthermore, persistent antibody lineages (observed both before and during treatment) showed higher SHM than lineages observed at only a single time point. Comparison of lineages between patients identified antibodies with high sequence similarity suggesting these antibodies may have arisen from convergent selection, i.e., different patients raising antibodies against shared or similar epitopes. These putative convergent antibodies were enriched in IgG2. IgG2 usage was also higher overall in durable responders than non-responders, even in samples taken prior to treatment. The higher levels of IgG2 observed in responders and in the potentially convergent sets of antibodies suggest that IgG2 antibodies may play a role in effective anti-tumor responses. In conclusion, our analysis of plasmablast repertoires from melanoma patients suggests that treatment with checkpoint inhibitors promotes SHM in durable responders, and that responder plasmablasts are enriched in IgG2. Moreover, patients make potentially convergent antibodies that are also enriched for the IgG2 subclass. Our observations demonstrate that the humoral immune response is remodeled in patients with anti-tumor responses and support a role for the humoral arm of the immune response in driving clinical benefit in patients treated with checkpoint inhibitors. Citation Format: Ngan Nguyen, Alusha Mamchak, Mariano Severgnini, Kevin S. Williamson, Xinqi Wu, Elliott F. Drabek, Michael Manos, Xiaomu Chen, Xiaobin Tang, Zoe Amiri, Chantia Carroll, Yvonne Leung, Dongkyoon Kim, Wayne Volkmuth, Norman Greenberg, Daniel Emerling, William H. Robinson, Guy Cavet, F. Stephen Hodi. Increased somatic hypermutation in the immunoglobulin sequences of melanoma patients who have durable response to checkpoint inhibitor therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 615.