http://www.bloodjournal.org/content/123/17/2625?sso-checked=true
Toxicities And Management: From CRS, CNS, And MAS/Hemophagocytic Lymphohistiocytosis To B-Cell AplasiaGiven the finding that, in most cases, cytokine release syndrome (CRS) seems to correlate with antitumor activity, one question that has emerged is the degree to which the innate immune system contributes to antitumor efficacy. In addition, we have shown that CRS is often accompanied by a macrophage activation syndrome (MAS), which may be driven in part by high levels of IL-6.37 Although it is straightforward to hypothesize that CAR T cells directly kill tumor cells, it is not entirely clear which cell type produces the vast majority of the cytokines, particularly IL-6 (which our work has demonstrated may be key to the toxicity response),37,51 and whether blockade of cytokines with anticytokine therapy such as tocilizumab or general immune suppression with corticosteroids affects the antitumor response. It is possible that the IL-6 is produced by the dying B cells, dying tumor cells, or activated macrophages that are recruited to digest lysed tumor cells.
Does interruption of the cytokine cascade lead to interruption of the antitumor effect? This remains an unanswered question and has direct clinical impact for patients and physicians deciding on when to abort the CRS. Furthermore, although, in our experience, most responding patients have some degree of CRS, it is not yet clear whether the severity of CRS or macrophage activation syndrome (MAS) is related to antitumor efficacy. The severity of CRS does appear to be related to the tumor burden. If engagement of the innate immune system contributes to the mechanism of action, this could bode well for the use of CAR T cells in solid tumors, where T cells may not preferentially home to and persist at the sites of tumors as efficiently as they do in hematologic malignancies.
Several patients in CD19-CAR trials across institutions have experienced obtundation, seizures, aphasia, and mental status changes, which have all been reversible. Some of these may be related to CRS, but whether this results from systemic cytokines crossing the blood-brain barrier and engaging cytokine receptors in the brain or from direct cytokine production in the central nervous system (CNS) is not clear. Many of these patients develop MAS, and MAS is often associated with neurologic toxicity.38⇓-40 In addition, we have unexpectedly found CAR T cells in the cerebrospinal fluid of asymptomatic patients, even when there is no evidence of CD19+ disease there. It is possible that the hyperthermia and IL-6 release during CRS enhances trafficking of CAR T cells to the cerebrospinal fluid in an antigen-independent mechanism.48 It is also possible that there is some cross-reactivity or as-yet-undetected expression of CD19 in the brain. Blinatumomab, a type of bispecific T-cell–engaging antibody (BiTE) that is a fusion protein between an anti-CD19 scFv and an anti-CD3 scFv, also has neurologic toxicity and seizures as its dose-limiting toxicity, even though it does not appear to control CNS disease. It is interesting that blinatumomab has also been shown to cause MAS.49 Optimistically, CAR T cells may provide a way of controlling occult or frank CNS malignancy without chemotherapy or radiotherapy.
B-cell aplasia is an expected on-target result of CD19-directed therapies and has served as useful surrogate to determine the persistence and effectiveness of CD19-directed CAR T cells. Fortunately, B-cell aplasia is a manageable disorder; patients may be infused with γ-globulin as replacement therapy, though this could become an expensive and difficult treatment to implement across all diseases that may be eventually treated with CAR T cells. Persistent B-cell aplasia could also result in an increased risk of infection even with replacement therapy. In an ideal setting, the CAR T cells would persist long enough to mediate definitive control of disease but then allow for recovery of normal B-cell and plasma cell recovery such that patients could be revaccinated.
As more patients are treated with CAR T cells directed to CD19, clinician investigators will need to establish straightforward algorithms for management of toxicities, including the optimal timing and dose of administration of cytokine blockade, corticosteroids, and immunoglobulin replacement.
Because gene-modified T cells are emerging as powerful therapies capable of effecting dramatic antitumor responses as well as significant toxicities,50strategies to incorporate suicide genes or abortive mechanisms may become necessary. This is especially true as CAR-directed T cells are further engineered to express cytokines and adjuvants51,52 that could act in transto amplify inflammatory cascades, or as CAR T cells directed to antigens with more widespread expression are tested. However, suicide systems are still difficult to implement in all CAR T-cell trials, because many of the suicide systems are immunogenic (eg, herpes simplex virus thymidine kinase) or require intravenous administration of the suicide-inducing prodrug.53Alternatively, altering the homing of T cells via enforced expression of chemokine receptors54 or pharmacologic blockade of chemokine receptors55 may be a strategy to both enhance efficacy and alleviate toxicity.
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