Pharmacologic strategies being explored for potential use in severe/refractory CRS/ICANS
| Therapeutic category . | Agent . | Mechanism of action . | FDA-approved indication . | Description of use with CRS/ICANS . | Prospective study in CRS/ICANS . |
|---|---|---|---|---|---|
| Anti-cytokine directed | Anakinra | IL-1 receptor antagonist | Reduction in signs/symptoms and to slow the progression of damage in adults with moderately to severely active RA who have failed ≥1 DMARDs, or for treatment of neonatal-onset multisystem inflammatory disorder. | Preclinical data supporting the role of IL-1 in mediating CRS/ICANS, alongside the impact of IL-1 blockade in treatment of CAR T-cell toxicities.41,42 Other clinical experience has been largely based on single-center/limited patient experiences and/or anecdotal reports. Has been used for treatment of refractory CRS/ICANs and HLH-like toxicities.20,43,55-57,91-95, Prospective studies are ongoing.30 Can be administered by IV or SC, with preference for IV administration in patients with edema in whom SC administration may not be as reliable. Given the short half-life with IV administration, more frequent dosing may be required.11 | NCT04148430 NCT04359784 NCT04150913 |
| Siltuximab | IL-6 antagonist | In adults, for the treatment of patients with multicentric Castleman disease who are HIV- and HHV-8–negative. | Mostly, the use has been limited to second-line or refractory CRS/ICANS after the use of multiple other agents. Limited data available.96,97 | NCT04975555 | |
| Emapalumab | IFN-γ–blocking antibody | For the treatment of adult and pediatric patients with primary HLH with refractory, recurrent, or progressive disease or intolerance to conventional HLH therapy. | Preclinical data supporting the role of IFN-γ in mediating CRS/ICANS, alongside the impact of IFN-γ blockade in treatment of CAR T-cell toxicities.98 Clinical experience is limited.66 | ||
| T-cell targeted | Antithymocyte globulin (ATG) | Direct T-cell targeting | For prophylaxis and treatment of acute rejection in patients receiving a kidney transplant, or use in conjunction with concomitant immunosuppression. | Potential use is based on clinical efficacy of targeting T cells. Data on CRS/ICANS are limited.99 Risk of infection/immunosuppression is high. | |
| Alemtuzumab (anti-CD52) | Depletion of T and B cells by binding to CD52 on the cell surface | For treatment of patients with relapsing forms of MS. | No published reports on its use for treatment of relapsed/refractory CRS/ICANS. Emerging use to facilitate engraftment of allogeneic or off-the-shelf CAR T cells.100,101 | ||
| Cyclophosphamide | Alkylating agent targeting T cells | Multiple indications for use in pediatrics and adults with malignancies and minimal change nephrotic syndrome. | Could be used for eradicating T cells. Limited experience (single case report) in the use for refractory CRS/ICANS.102 | ||
| TKIs103 | Dasatinib | TKI (BCR-ABL) | For adults in chronic, accelerated, or blast phase of Ph+ CML; for adults with Ph+ ALL. | Preclinical studies demonstrate the ability of dasatinib to suppress CAR T-cell cytotoxicity, cytokine secretion, and proliferation.104,105 | NCT04603872 |
| Ibrutinib | BTK inhibitor | For adults with MCL who have received at least 1 prior therapy, for CLL with 17p deletion, or in those who have received at least 1 prior therapy or who have Waldenstrom macroglobulinemia. | Based on the role of ibrutinib to inhibit IL-2–induced tyrosine kinases, there is evidence of reduction in cytokine production in a preclinical model of CD19 CAR T cells.106 Emerging clinical data incorporating ibrutinib suggest the potential of reducing CRS severity.32 | NCT03960840 | |
| Ruxolitinib or alternative JAK1 inhibitors | JAK inhibitor | For treatment of adults with myelofibrosis and polycythemia vera. For treatment of adults and pediatric patients aged >12 y with steroid refractory acute GVHD or chronic GVHD after failure of >1-2 lines of systemic therapy. | Preclinical studies demonstrate a role of JAK pathway singling blockade and dose-dependent reduction of multiple cytokines implicated in CRS.107 Patient experience for use in CRS/ICANS is limited to case reports.108,109 | ||
| CAR T-cell construct–based safety switches | Based on the CAR T-cell construct and the incorporation of either suicide switches (eg, inducible Caspase 9 targeted by the synthetic dimerizing drug rimiducid)110 alternative transcriptional controls,111 or truncated-targetable receptors (eg, EGFR or CD20) that can be targeted by monoclonal antibodies (eg, cetuximab or rituximab), these agents can be considered for use when eradicating the CAR T cell in the setting of refractory and when life-threatening CAR T-cell–mediated toxicities are present. The clinical use and experience to date are limited. | ||||
| Therapeutic category . | Agent . | Mechanism of action . | FDA-approved indication . | Description of use with CRS/ICANS . | Prospective study in CRS/ICANS . |
|---|---|---|---|---|---|
| Anti-cytokine directed | Anakinra | IL-1 receptor antagonist | Reduction in signs/symptoms and to slow the progression of damage in adults with moderately to severely active RA who have failed ≥1 DMARDs, or for treatment of neonatal-onset multisystem inflammatory disorder. | Preclinical data supporting the role of IL-1 in mediating CRS/ICANS, alongside the impact of IL-1 blockade in treatment of CAR T-cell toxicities.41,42 Other clinical experience has been largely based on single-center/limited patient experiences and/or anecdotal reports. Has been used for treatment of refractory CRS/ICANs and HLH-like toxicities.20,43,55-57,91-95, Prospective studies are ongoing.30 Can be administered by IV or SC, with preference for IV administration in patients with edema in whom SC administration may not be as reliable. Given the short half-life with IV administration, more frequent dosing may be required.11 | NCT04148430 NCT04359784 NCT04150913 |
| Siltuximab | IL-6 antagonist | In adults, for the treatment of patients with multicentric Castleman disease who are HIV- and HHV-8–negative. | Mostly, the use has been limited to second-line or refractory CRS/ICANS after the use of multiple other agents. Limited data available.96,97 | NCT04975555 | |
| Emapalumab | IFN-γ–blocking antibody | For the treatment of adult and pediatric patients with primary HLH with refractory, recurrent, or progressive disease or intolerance to conventional HLH therapy. | Preclinical data supporting the role of IFN-γ in mediating CRS/ICANS, alongside the impact of IFN-γ blockade in treatment of CAR T-cell toxicities.98 Clinical experience is limited.66 | ||
| T-cell targeted | Antithymocyte globulin (ATG) | Direct T-cell targeting | For prophylaxis and treatment of acute rejection in patients receiving a kidney transplant, or use in conjunction with concomitant immunosuppression. | Potential use is based on clinical efficacy of targeting T cells. Data on CRS/ICANS are limited.99 Risk of infection/immunosuppression is high. | |
| Alemtuzumab (anti-CD52) | Depletion of T and B cells by binding to CD52 on the cell surface | For treatment of patients with relapsing forms of MS. | No published reports on its use for treatment of relapsed/refractory CRS/ICANS. Emerging use to facilitate engraftment of allogeneic or off-the-shelf CAR T cells.100,101 | ||
| Cyclophosphamide | Alkylating agent targeting T cells | Multiple indications for use in pediatrics and adults with malignancies and minimal change nephrotic syndrome. | Could be used for eradicating T cells. Limited experience (single case report) in the use for refractory CRS/ICANS.102 | ||
| TKIs103 | Dasatinib | TKI (BCR-ABL) | For adults in chronic, accelerated, or blast phase of Ph+ CML; for adults with Ph+ ALL. | Preclinical studies demonstrate the ability of dasatinib to suppress CAR T-cell cytotoxicity, cytokine secretion, and proliferation.104,105 | NCT04603872 |
| Ibrutinib | BTK inhibitor | For adults with MCL who have received at least 1 prior therapy, for CLL with 17p deletion, or in those who have received at least 1 prior therapy or who have Waldenstrom macroglobulinemia. | Based on the role of ibrutinib to inhibit IL-2–induced tyrosine kinases, there is evidence of reduction in cytokine production in a preclinical model of CD19 CAR T cells.106 Emerging clinical data incorporating ibrutinib suggest the potential of reducing CRS severity.32 | NCT03960840 | |
| Ruxolitinib or alternative JAK1 inhibitors | JAK inhibitor | For treatment of adults with myelofibrosis and polycythemia vera. For treatment of adults and pediatric patients aged >12 y with steroid refractory acute GVHD or chronic GVHD after failure of >1-2 lines of systemic therapy. | Preclinical studies demonstrate a role of JAK pathway singling blockade and dose-dependent reduction of multiple cytokines implicated in CRS.107 Patient experience for use in CRS/ICANS is limited to case reports.108,109 | ||
| CAR T-cell construct–based safety switches | Based on the CAR T-cell construct and the incorporation of either suicide switches (eg, inducible Caspase 9 targeted by the synthetic dimerizing drug rimiducid)110 alternative transcriptional controls,111 or truncated-targetable receptors (eg, EGFR or CD20) that can be targeted by monoclonal antibodies (eg, cetuximab or rituximab), these agents can be considered for use when eradicating the CAR T cell in the setting of refractory and when life-threatening CAR T-cell–mediated toxicities are present. The clinical use and experience to date are limited. | ||||
Given the concern for increasing risk of infection with incorporation of additional agents, caution is advised against the simultaneous administration of multiple strategies.
There are currently no evidence-based guidelines or proven strategies that exist for the treatment of CRS/ICANS that is persistent or progressive after intervention with tocilizumab and corticosteroids. The table represents a list of potential agents that have been considered based on single-institutional or limited patient experiences, preclinical data, established T-cell–directed mechanism of action, or adopted for use based on efficacy in alternative hyperinflammatory settings. FDA-approved package inserts for several commercial CAR T-cell constructs advise the use of implementing alternative strategies with grade 4 CRS (eg, anakinra, siltuximab, ruxolitinib, cyclophosphamide, IVIG, and ATG).
ALL, acute lymphoblastic leukemia; BCR, B-cell receptor; BTK, Bruton tyrosine kinase; CML, chronic myelogenous leukemia; DMARDs, disease-modifying antirheumatic drugs; EGFR, epidermal growth factor receptor; GVHD, graft-versus-host disease; IFN-γ, interferon gamma; JAK, Janus kinase; MCL, mantle cell lymphoma; MS, multiple sclerosis; RA, rheumatoid arthritis; TKI, tyrosine kinase inhibitor.