Toxicity management for patients receiving novel T-cell engaging therapies

Abstract

Purpose of review: 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.

Recent findings: 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.

Summary: 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.

FIGURE 1

The chimeric antigen receptor consists of the single chain variable fragment of an antibody (scFv) that recognizes the CD19 protein on B cells and leukemia cells coupled to the CD3 zeta activation domain and costimulatory domains from CD28 and/or 4-1BB. This combines the major histocompatibility complex (MHC)-recognition of a tumor antigen with the activating potential of the T-cell receptor, allowing redirection of T cells to leukemia. Reproduced with permission from Sue Seif.