Currently used interventions to mitigate CAR T-cell toxicities and relative mechanism of action and indications
| Targeted biological entities . | Therapeutic agents . | Mechanism of action . | Strategies . | Clinical trials . |
|---|---|---|---|---|
| Immune cell targeted | Corticosteroids (dexamethasone and methylprednisolone) | Glucocorticoid receptor agonist | Prophylactic: CRS/ICANS. Prophylactic dexamethasone 10 mg given on day 0, 1, and 2 after CAR infusion resulted in no grade 3 or higher CRS and a low rate of neurologic events in this study population.85 | NCT05459571, active not recruiting |
| Therapeutic: first line for treatment of CRS/ICANS. Grade 2-3 CRS/ICANS: dexamethasone 10 mg every 6-12 h (or methylprednisolone equivalent). Grade 4 CRS/ICANS: high-dose methylprednisolone 500 mg bid.3 | ||||
| IL-1 | Anakinra | IL-1 receptor antagonist | Prophylactic: CRS/ICANS. Under investigation, phase 2 results show a lower incidence of ICANS.95,96 There are active and recruiting trials ongoing. | NCT04359784, recruiting NCT04205838, recruiting NCT04148430, active not recruiting NCT04432506, active not recruiting |
| Therapeutic: steroid-refractory high-grade ICANS. Data are limited.86 | ||||
| IL-6 | Tocilizumab | IL-6 receptor antagonist | Prophylactic: CRS/ICANS. In ZUMA-1, tocilizumab used on day 2 may reduce the incidence of severe CRS but not the incidence of severe neurological events.97 | |
| Therapeutic: first line for CRS. Grade 2-4 CRS tocilizumab 8 mg/kg is administered >1 h (not to exceed 800 mg per dose). Repeat every 8 h if no improvement in CRS; limit to a maximum of 3 doses in 24 h and 4 doses total. Tocilizumab is FDA approved for use in CRS, but is not effective for isolated ICANS, and may be associated with worsening neurotoxicity.87 | ||||
| Siltuximab | IL-6 antagonist | Prophylactic: CRS/ICANS. Data from the phase 1 study showed no dose-limiting toxicities associated with single-dose siltuximab prophylaxis before CAR infusion.98 | ||
| Therapeutic: refractory CRS/ICANS, limited data during national tocilizumab shortage suggests use is safe and feasible.99 There is an active and recruiting trial ongoing for further investigation. | NTC04975555, recruiting | |||
| TNF-α | Etanercept | TNF-α blocking antibody | Therapeutic: data limited to case series; further studies are needed.100 | |
| IFN-γ | Emapalumab | IFN-γ– blocking antibody | Therapeutic: FDA approved for primary HLH. Limited data for CRS/ICANS/HLH to case series.88 | |
| TKI | Dasatinib | BCR-Abl, Src, c-Kit, among others, multikinase inhibitor | Prophylactic: CRS/ICANS. Data are limited to case report. There is an active and recruiting clinical trial investigating the combination of CD19/BCMA-targeted T cells combined with dasatinib. | NCT04603872, recruiting |
| Ibrutinib | BTK inhibitor: inhibits IL-2–induced TKIs | Prophylactic: CRS/ICANS. Data are limited to a pilot study. CLL patients treated with CAR therapy combined with ibrutinib were associated with lower CRS severity and lower serum concentrations of CRS-associated cytokines despite equivalent in vivo CAR T-cell expansion.89 | ||
| Ruxolitinib | JAK inhibitor: pathway signaling blockade of multiple cytokines | Therapeutic: grade 3-4 steroid-refractory CRS. Limited data from a case report and pilot study suggests ruxolitinib is active in severe CRS without impairing the antitumor effect.90,91 | ||
| Itacitinib | JAK inhibitor: pathway signaling blockade of multiple cytokines | Prophylactic: CRS/ICAN, limited data from a preclinical study and a phase 2 study suggest prophylactic itacitinib reduced the onset and severity of CRS and ICANS.92,101 (NCT04071366). There is an active and recruiting trial. | NCT05757219, recruiting | |
| T-cell targeted | Antithymocyte globulin | Direct T-cell targeting | Therapeutic: severe CRS/ICANS. Limited data from the ZUMA-2 trial of patient with severe grade 4 ICANS with cerebral edema which resolved after intervention including ATG.93 | |
| Cyclophosphamide | Alkylating agent, direct T-cell targeting | Therapeutic: severe refractory CRS/ICANS. Data are limited to case report of posterior reversible encephalopathy syndrome after CAR therapy.102 | ||
| CAR T-cell targeted | CAR constructs safety switches (iC9, HSV-TK, CD20, EGFRt, among others). | Suicide switches (iC9), truncated target receptors targeted by monoclonal antibodies | Therapeutic: limited clinical data for iC9 safety switch in haploidentical adoptive modified stem-cell transplant.103 Limited case report data for iC9 safety switch for the treatment of severe and steroid-refractory grade 4 ICANS.94 There are active and recruiting trials investigating CAR construct safety switches for the treatment of CRS/ICANS. | NCT03016377, recruiting NCT03696784, recruiting |
| Pan-cytokine targeted | Hemofiltration, plasmapheresis | Whole plasma | Therapeutic: severe refractory CRS/ICANS. Data are limited to case report.104 |
| Targeted biological entities . | Therapeutic agents . | Mechanism of action . | Strategies . | Clinical trials . |
|---|---|---|---|---|
| Immune cell targeted | Corticosteroids (dexamethasone and methylprednisolone) | Glucocorticoid receptor agonist | Prophylactic: CRS/ICANS. Prophylactic dexamethasone 10 mg given on day 0, 1, and 2 after CAR infusion resulted in no grade 3 or higher CRS and a low rate of neurologic events in this study population.85 | NCT05459571, active not recruiting |
| Therapeutic: first line for treatment of CRS/ICANS. Grade 2-3 CRS/ICANS: dexamethasone 10 mg every 6-12 h (or methylprednisolone equivalent). Grade 4 CRS/ICANS: high-dose methylprednisolone 500 mg bid.3 | ||||
| IL-1 | Anakinra | IL-1 receptor antagonist | Prophylactic: CRS/ICANS. Under investigation, phase 2 results show a lower incidence of ICANS.95,96 There are active and recruiting trials ongoing. | NCT04359784, recruiting NCT04205838, recruiting NCT04148430, active not recruiting NCT04432506, active not recruiting |
| Therapeutic: steroid-refractory high-grade ICANS. Data are limited.86 | ||||
| IL-6 | Tocilizumab | IL-6 receptor antagonist | Prophylactic: CRS/ICANS. In ZUMA-1, tocilizumab used on day 2 may reduce the incidence of severe CRS but not the incidence of severe neurological events.97 | |
| Therapeutic: first line for CRS. Grade 2-4 CRS tocilizumab 8 mg/kg is administered >1 h (not to exceed 800 mg per dose). Repeat every 8 h if no improvement in CRS; limit to a maximum of 3 doses in 24 h and 4 doses total. Tocilizumab is FDA approved for use in CRS, but is not effective for isolated ICANS, and may be associated with worsening neurotoxicity.87 | ||||
| Siltuximab | IL-6 antagonist | Prophylactic: CRS/ICANS. Data from the phase 1 study showed no dose-limiting toxicities associated with single-dose siltuximab prophylaxis before CAR infusion.98 | ||
| Therapeutic: refractory CRS/ICANS, limited data during national tocilizumab shortage suggests use is safe and feasible.99 There is an active and recruiting trial ongoing for further investigation. | NTC04975555, recruiting | |||
| TNF-α | Etanercept | TNF-α blocking antibody | Therapeutic: data limited to case series; further studies are needed.100 | |
| IFN-γ | Emapalumab | IFN-γ– blocking antibody | Therapeutic: FDA approved for primary HLH. Limited data for CRS/ICANS/HLH to case series.88 | |
| TKI | Dasatinib | BCR-Abl, Src, c-Kit, among others, multikinase inhibitor | Prophylactic: CRS/ICANS. Data are limited to case report. There is an active and recruiting clinical trial investigating the combination of CD19/BCMA-targeted T cells combined with dasatinib. | NCT04603872, recruiting |
| Ibrutinib | BTK inhibitor: inhibits IL-2–induced TKIs | Prophylactic: CRS/ICANS. Data are limited to a pilot study. CLL patients treated with CAR therapy combined with ibrutinib were associated with lower CRS severity and lower serum concentrations of CRS-associated cytokines despite equivalent in vivo CAR T-cell expansion.89 | ||
| Ruxolitinib | JAK inhibitor: pathway signaling blockade of multiple cytokines | Therapeutic: grade 3-4 steroid-refractory CRS. Limited data from a case report and pilot study suggests ruxolitinib is active in severe CRS without impairing the antitumor effect.90,91 | ||
| Itacitinib | JAK inhibitor: pathway signaling blockade of multiple cytokines | Prophylactic: CRS/ICAN, limited data from a preclinical study and a phase 2 study suggest prophylactic itacitinib reduced the onset and severity of CRS and ICANS.92,101 (NCT04071366). There is an active and recruiting trial. | NCT05757219, recruiting | |
| T-cell targeted | Antithymocyte globulin | Direct T-cell targeting | Therapeutic: severe CRS/ICANS. Limited data from the ZUMA-2 trial of patient with severe grade 4 ICANS with cerebral edema which resolved after intervention including ATG.93 | |
| Cyclophosphamide | Alkylating agent, direct T-cell targeting | Therapeutic: severe refractory CRS/ICANS. Data are limited to case report of posterior reversible encephalopathy syndrome after CAR therapy.102 | ||
| CAR T-cell targeted | CAR constructs safety switches (iC9, HSV-TK, CD20, EGFRt, among others). | Suicide switches (iC9), truncated target receptors targeted by monoclonal antibodies | Therapeutic: limited clinical data for iC9 safety switch in haploidentical adoptive modified stem-cell transplant.103 Limited case report data for iC9 safety switch for the treatment of severe and steroid-refractory grade 4 ICANS.94 There are active and recruiting trials investigating CAR construct safety switches for the treatment of CRS/ICANS. | NCT03016377, recruiting NCT03696784, recruiting |
| Pan-cytokine targeted | Hemofiltration, plasmapheresis | Whole plasma | Therapeutic: severe refractory CRS/ICANS. Data are limited to case report.104 |
ATG, antithymocyte globulin; BCR-Abl, Ph chromosome; bid, twice daily; BTK, Bruton tyrosine kinase; c-Kit, proto-oncogene receptor tyrosine kinase; CLL, chronic lymphocytic leukemia; EGFRt, epidermal growth factor receptor; FDA, US Food and Drug Administration; HLH, hemophagocytic lymphohistiocystosis; HSV-TK, herpes simplex virus thymidine kinase; iC9, inducible caspase 9; Src, proto-oncogene tyrosine-protein kinase; TKI, tyrosine kinase inhibitor; TNF-α, tumor necrosis factor-α; ZUMA-1, phase 1/2, single-arm, multicenter study of axicabtagene ciloleucel in patients with refractory large B-cell lymphoma.