Utility of a safety switch to abrogate CD19.CAR T-cell–associated neurotoxicity

Abstract

Chimeric antigen receptor (CAR)-modified T cells targeting the CD19 antigen are approved to treat relapsed and refractory B-cell malignancies. [1][2][3][4] Despite durable objective responses, most patients experience acute toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). 5 Although many cases of ICANS resolve with supportive measures, high-grade ICANS may result in status epilepticus, lasting neurologic deficits, cerebral edema, 6 and death. 7 Therefore, novel approaches for severe ICANS fill an urgent unmet need to enhance the use of adoptive cellular therapy.15. Diaconu I, Ballard B, Zhang M, et al. Inducible caspase-9 selectively modulates the toxicities of CD19-specific chimeric antigen receptormodified T cells.

Mechanisms of cytokine release syndrome and neurotoxicity of CAR T-cell therapy and associated prevention and management strategies

“…iCasp9 is an apoptosis-triggering fusion protein, and rimiducid (AP1903) can induce the dimerization of iCasp9 and activate downstream caspase, eliminating the engineered CAR T-cells within 30 min [136,137]. This strategy induced dramatic and immediate CAR T-cell elimination in a 26-year-old female, effectively alleviating the ICANS symptoms and improving the ICANS grades (from 3 to 1) and the Immune Effector Cell-Associated Encephalopathy (ICE) score (from 0 to 7) within 12 h [138]. The efficacy of iCasp9 CAR T-cells in CD19 B cell malignancies is still being evaluated in clinical trials (NCT03016377 and NCT03696784).…”

Manufacturing CD20/CD19-targeted iCasp9 regulatable CAR-TSCMcells usingqCART, theQuantum pBac-based CAR-T system

“…Recently, Foster et al (2021) has demonstrated that acute ICANS can be effectively controlled by treating CAR-T therapy patients with the iCasp9-activating agent, rimiducidn. 23 We included an iCasp9 safety switch in our GF-CART01 design to mitigate the tumorigenicity risk associated with genetic manipulation, and we confirmed that CAR-T cells can be eliminated upon AP1903 drug treatment.…”

Cytokine Release Syndrome and Associated Acute Toxicities in Pediatric Patients Undergoing Immune Effector Cell Therapy or Hematopoietic Cell Transplantation

“…In patients who do not respond to these measures, third-line agents should be entertained, including Siltuximab ( 63 ), Anakinra ( 29 , 64 ) and high-dose Methylprednisolone (1gram daily x 3days, followed by rapid taper) ( 55 ). In products containing an inducible safety switch such as inducible caspase-9 (iC9) ( 65 ) this should be triggered in the face of serious uncontrollable toxicity. Although clinical data is lacking, preclinical models have suggested that the tyrosine kinase inhibitor Dasatinib may be utilized to transiently ablate CAR signaling by interfering with the lymphocyte-specific protein tyrosine kinase (LCK) and inhibiting phosphorylation of the CD3ζ-chain contained in the CAR ( 66 ) ( Figure 2 ).…”