Toxicity and management in CAR T-cell therapy

Abstract

T cells can be genetically modified to target tumors through the expression of a chimeric antigen receptor (CAR). Most notably, CAR T cells have demonstrated clinical efficacy in hematologic malignancies with more modest responses when targeting solid tumors. However, CAR T cells also have the capacity to elicit expected and unexpected toxicities including: cytokine release syndrome, neurologic toxicity, “on target/off tumor” recognition, and anaphylaxis. Theoretical toxicities including clonal expansion secondary to insertional oncogenesis, graft versus host disease, and off-target antigen recognition have not been clinically evident. Abrogating toxicity has become a critical step in the successful application of this emerging technology. To this end, we review the reported and theoretical toxicities of CAR T cells and their management.

Axicabtagene ciloleucel, a first-in-class CAR T cell therapy for aggressive NHL

“…Greater induction of IL-15 was associated with response to treatment [32,36,48]. C-reactive protein (CRP), an inflammatory marker produced by hepatocytes in response to IL-6 [51], has been shown to peak 3-5 d after CAR T cell infusion [37,40]. Granzyme B, an effector serine protease and key mediator of T cell cytotoxic effects, and IL-10, an inflammatory/immune-modulating cytokine, have been shown to peak at day 6-7 post-CAR T cell infusion [50], and higher peak levels of IL-10 have been associated with CR and PR vs. stable and progressive disease [32].…”

“…As a form of adoptive cell transfer, anti-CD19 CAR T cell therapy has the capacity to elicit a class-specific set of adverse events (AEs) [51]. The most concerning acute toxicities, occurring within hours to a few days after infusion of CAR T cells, namely CRS and NEs, are generally reversible and usually resolve within 2 weeks without lasting sequelae in the majority of patients [35,40,51,52].…”

“…The most concerning acute toxicities, occurring within hours to a few days after infusion of CAR T cells, namely CRS and NEs, are generally reversible and usually resolve within 2 weeks without lasting sequelae in the majority of patients [35,40,51,52]. Clinical manifestations of CRS can be evident within 12 h after infusion, and initial symptoms include fever, and constitutional symptoms.…”

“…CRS is thought to result from widespread and simultaneous activation of T cells and the subsequent release of soluble inflammatory mediators, such as cytokines, chemokines, and immune effector molecules [51]. Similarly, although the underlying mechanism of NEs in CAR T therapy is not fully understood, emerging data indicate a correlation with elevated inflammatory cytokines [51,54].…”

The Flipside of the Power of Engineered T Cells: Observed and Potential Toxicities of Genetically Modified T Cells as Therapy

“…Toxicities discussed here included bystander effects leading to systemic inflammatory reactions such as the previously described cytokine release syndrome (CRS), neurologic toxicities, on-and offtarget effects of CARs, hypersensitivity reactions to CAR constructs, and theoretical toxicities, including insertional mutagenesis mediated by transgene delivery, autonomous CAR signaling, autoimmunity or graft-versus-host disease (GVHD) caused by T cell products, and generation of a replication-competent virus ( Figure 1). 1,2 Despite the focus on toxicities in this review, we remain optimistic that toxicity mitigation can be overcome through experience in clinical management and optimized T cell engineering strategies, while some of the theoretical toxicities may never materialize in the clinical setting.…”