Abstract
BackgroundTh17 cells are CD4+ cells that produce interleukin 17 (IL-17) and are potent inducers of tissue inflammation and autoimmunity. We studied the levels of this T cell subset in peripheral blood of patients treated with the anti-CTLA4 antibody tremelimumab since its major dose limiting toxicities are inflammatory and autoimmune in nature.MethodsPeripheral blood mononuclear cells (PBMC) were collected before and after receiving tremelimumab within two clinical trials, one with tremelimumab alone (21 patients) and another together with autologous dendritic cells (DC) pulsed with the melanoma epitope MART-126–35 (6 patients). Cytokines were quantified directly in plasma from patients and after in vitro stimulation of PBMC. We also quantified IL-17 cytokine-producing cells by intracellular cytokine staining (ICS).ResultsThere were no significant changes in 13 assayed cytokines, including IL-17, when analyzing plasma samples obtained from patients before and after administration of tremelimumab. However, when PBMC were activated in vitro, IL-17 cytokine in cell culture supernatant and Th17 cells, detected as IL-17-producing CD4 cells by ICS, significantly increased in post-dosing samples. There were no differences in the levels of Th17 cells between patients with or without an objective tumor response, but samples from patients with inflammatory and autoimmune toxicities during the first cycle of therapy had a significant increase in Th17 cells.ConclusionThe anti-CTLA4 blocking antibody tremelimumab increases Th17 cells in peripheral blood of patients with metastatic melanoma. The relation between increases in Th17 cells and severe autoimmune toxicity after CTLA4 blockade may provide insights into the pathogenesis of anti-CTLA4-induced toxicities.Trial RegistrationClinical trial registration numbers: NCT0090896 and NCT00471887
Highlights
Monoclonal antibodies blocking the cytotoxic T lymphocyte associated antigen 4 (CTLA4), a key negative regulator of the immune system, induce regression of tumors in mice and humans, and are being pursued as treatment for cancer [1,2,3,4]
The emerging clinical data suggests that a minority of patients with metastatic melanoma achieve durable objective tumor responses when treated with CTLA4 blocking monoclonal antibodies, with most being relapse-free up to 7 years later
Six patients were treated in a phase I clinical trial of three biweekly intradermal (i.d.) administrations of a fixed dose of 1 × 107 autologous dendritic cells (DC) pulsed with the MART126–35 immunodominant peptide epitope (MART-126–35/ DC) manufactured as previously described [21], concomitantly with a dose escalation of tremelimumab at 10 (3 patients) and 15 mg/kg (3 other patients) every 3 months (UCLA IRB# 03-12-023, Investigator New Drug (IND)# 11579, Trial Registration number NCT0090896)
Summary
Monoclonal antibodies blocking the cytotoxic T lymphocyte associated antigen 4 (CTLA4), a key negative regulator of the immune system, induce regression of tumors in mice and humans, and are being pursued as treatment for cancer [1,2,3,4]. The emerging clinical data suggests that a minority of patients with metastatic melanoma (in the range of 10%) achieve durable objective tumor responses when treated with CTLA4 blocking monoclonal antibodies, with most being relapse-free up to 7 years later. There is a prevalent thought that toxicity and response are correlated after therapy with anti-CTLA4 blocking monoclonal antibodies This conclusion is based mainly on statistical correlations in 2 × 2 tables grouping patients with toxicities and/ or objective responses. We studied a differentiated subset of cells termed Th17, which have emerged as key mediators of autoimmunity and inflammation for their potential implication in toxicity and responses after anti-CTLA4 therapy. We studied the levels of this T cell subset in peripheral blood of patients treated with the anti-CTLA4 antibody tremelimumab since its major dose limiting toxicities are inflammatory and autoimmune in nature
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