title: Toxicity management for patients receiving novel T-cell engaging therapies.
abstract: OBJECTIVE
  Recent clinical trials using T-cell engaging immunotherapies such as bispecific antibodies which target T cells and tumor cells, as well as engineered T cells that express targeting and activation molecules known as chimeric antigen receptors, have demonstrated powerful proof of concept. These therapies result in a significant degree of immune activation in the patient, which has correlated with greatly increased efficacy but also with notable toxicity. These therapies produce nonphysiologic T-cell activation, which is the hallmark of these new, highly active treatments.
  
  
  RESULTS
  We and others have noted cytokine activation profiles that correlate with both toxicity and efficacy in patients receiving T-cell engaging therapies. Effector cytokines such as interferon-γ are elevated, but so are cytokines that are associated with macrophage activation syndrome/hemophagocytic lymphohistiocytosis, such as interleukin (IL)-10 and IL-6. Although corticosteroids can control some of these toxicities, a targeted approach may produce superior toxicity control without interfering with efficacy. One approach we have developed targets IL-6, a key cytokine in the toxicity response, using the IL-6 receptor antagonist tocilizumab.
  
  
  CONCLUSIONS
  Detailed studies of the T-cell activation produced by these novel therapies has led to more targeted approaches that have the potential to control toxicity while maintaining efficacy.
authors.affiliation: Division of Pediatric Oncology, Children's Hospital of Philadelphia, University of Pennsylvania, Perelman School of Medicine, Pennsylvania, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Barrett
authors.forename: David T
authors.initials: DT
authors.lastname: Teachey
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Grupp
mesh_terms: D018033:Antibodies, Bispecific / Q000009:adverse effects; D018941:Antigens, CD19 / Q000276:immunology; D002648:Child; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D007154:Immune System Diseases / Q000276:immunology; D007167:Immunotherapy / Q000009:adverse effects* / Q000379:methods; D008213:Lymphocyte Activation / Q000276:immunology; D051359:Lymphohistiocytosis, Hemophagocytic / Q000276:immunology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology / Q000628:therapy; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013577:Syndrome; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D018033:Antibodies, Bispecific; D018941:Antigens, CD19; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; C510808:blinatumomab