Development of thyroglobulin antibodies after GVAX immunotherapy is associated with prolonged survival

Abstract

Cancer immunotherapy induces a variety of autoinflammatory responses, including those against the thyroid gland, which can be exploited to predict clinical outcomes. Considering the paucity of information about thyroid autoimmunity in patients receiving cancer vaccines, we designed our study to assess the development of thyroglobulin antibodies (TgAbs) in patients treated with GVAX (vaccine made of a tumor cell type transfected with GM-CSF) and/or ipilimumab and correlated seroconversion with survival. Using both in house and commercial ELISA assays, we measured TgAbs in patients with pancreatic (No.-‰=-‰53), prostate (No.-‰=-‰35) or colon (No.-‰=-‰8) cancer, before and after treatment with GVAX only (No.-‰=-‰34), GVAX plus ipilimumab (No.-‰=-‰42) or ipilimumab (No.-‰=-‰20), and correlated their levels with patient's survival, disease status and T-cell surface markers. Antibodies to thyroperoxidase, myeloperoxidase, proteinase 3, insulin and actin were also measured. TgAbs specifically developed after GVAX, independent of the underlying cancer (81% in prostate, 75% colon cancer and 76% pancreatic cancer) and co-administration of ipilimumab (75% in GVAX only and 78% in GVAX plus ipilimumab). This TgAbs seroconversion could be detected mainly by the in house assay, suggesting that the thyroglobulin epitopes recognized by the antibodies induced by GVAX are different from the epitopes seen in the classic form of Hashimoto thyroiditis. Notably, TgAbs seroconversion was associated with significantly prolonged survival (p-‰=-‰0.01 for pancreas and p-‰=-‰0.005 for prostate cancer). In conclusion, GVAX immunotherapy induces the appearance of TgAbs that recognize a unique antigenic repertoire and associate with prolonged survival. What's new? Auto-inflammatory responses against the thyroid gland can develop in association with cancer immunotherapy, but little is known about the mechanism or significance of immunotherapy-related autoimmune thyroiditis. Here, the production of thyroglobulin antibodies (TgAbs) in response to treatment with the vaccine GVAX, administered either alone or in association with the immunotherapeutic antibody ipilimumab, was explored in pancreatic, prostate, and colon cancer patients. TgAbs were produced specifically following GVAX immunotherapy and were found to recognize unique antigenic epitopes. TgAbs production also was associated with improved overall survival, suggesting that it may be a useful predictive tool in the clinical setting.