| Cancer is an incredibly challenging disease to treat because tumors resemble normal, healthy tissue. Several approaches to treat cancer have been developed, including chemotherapy, radiotherapy, targeted therapies, and immunotherapy. Combination of therapies with unique mechanisms of action may prove to be the best way to cure patients of this devastating disease. Here we describe the efficacy of combinations of different types of immunotherapy in the murine B16 melanoma model, and focus on an unexpected side effect of one of these therapies, the T cell-targeting antibody DTA1. Immunotherapy using antibodies to enhance T cell function has been successful in recent clinical trials. Many molecules that improve activation and effector function of T cells have been investigated as potential new targets for immunomodulatory antibodies, including the tumor necrosis factor receptor (TNFR) superfamily members GITR and OX40. Antibodies engaging GITR or OX40 result in significant tumor protection in preclinical models. In this study, we observed that the GITR agonist antibody DTA-1 causes anaphylaxis in mice upon repeated intraperitoneal dosing. DTA-1-induced anaphylaxis requires GITR, CD4+ T cells, B cells, and IL-4. Transfer of serum antibodies from DTA-1-treated mice, which contain high levels of DTA-1specific IgGI, can induce anaphylaxis in naive mice upon administration of an additional dose of DTA-1, suggesting that anaphylaxis results from anti-DTA-1 antibodies. Depletion of basophils and blockade of platelet activating factor, the key components of the IgG1 pathway of anaphylaxis, rescues the mice from DTA-1-induced anaphylaxis. These results demonstrate a previously undescribed lethal side effect of repetitive doses of an agonist immunomodulatory antibody as well as insight into the mechanism of toxicity, which may offer a means of preventing adverse effects in future clinical trials using anti-GITR or other agonist antibodies as immunotherapies. |
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