Third-generation CAR T-cells incorporating a TLR2 co-stimulatory domain combine enhanced cytotoxicity with reduced inflammatory cytokine production: Pre-clinical and phase 1 clinical trial findings (EHA-EBMT-CART 2023)
Registry data suggest a CD28-costimulated anti-CD19 CAR T-cell product (axi-cel, 1928z) results in higher response rates, but increased neurotoxicity and severe cytokine release syndrome (CRS), than a 41BB-costimulated product (tisa-cel, 19BBz)...In an ongoing phase 1 dose-escalation trial, we administered fludarabine and cyclophosphamide lymphodepletion followed by 5 × 104/kg to 1 × 106/kg 1928T2z CAR T-cells to 19 patients with relapsed or refractory B-cell non-Hodgkin lymphomas...* = P<0.05, ** = P<0.01, *** = P<0.001, **** = P<0.0001.ParticipantLymphoma subtypeDose(1928T2z CAR T-cells/kg)CRS(highest grade)ICANS(highest grade)3 month responseEN1-01EN1-02EN1-03EN1-04EN1-05EN1-07EN1-12EN1-13EN1-14EN1-08EN1-15EN1-16EN1-17EN1-18EN1-20EN1-21EN1-22EN1-23EN1-24FLMCLDHLFLDLBCLDHLDLBCLDLBCLDLBCLDLBCLtFLPMBCLtFLDLBCLTHRLBCLDLBCLDLBCLFLDLBCL5 × 1045 × 1045 × 1041 × 1051 × 1051 × 1052 × 1052 × 1052 × 1055 × 1055 × 1055 × 1055 × 1055 × 1055 × 1051 × 1061 × 1061 × 1061 × 10612NoneNone1None2111NoneNoneNoneNone2*111NoneNoneNoneNoneNoneNoneNoneNoneNoneNoneNoneNoneNoneNoneNoneNoneNoneNoneNoneNonePDPDCRCRCRCRPDPDCRPDPRCRCRPDPDCRCRPendingPendingCR, complete response; CRS, cytokine release syndrome; DHL, double hit lymphoma; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; MCL, mantle cell lymphoma; PD, progressive disease; PMBCL, primary mediastinal large B-cell lymphoma; PR, partial response; tFL, transformed follicular lymphoma; THRLBCL, T-cell/histiocyte rich large B-cell lymphoma; ICANS, immune effector cell-associated neurotoxicity syndrome; *Grade 1 CRS at day 6, then grade 2 CRS at day 122 following pembrolizumab administration for recurrent lymphoma. In conclusion, a third-generation anti-CD19 CAR T-cell construct combining CD28 and TLR2-derived co-stimulatory domains has the potential to combine high efficacy with low rates of severe CRS and of neurotoxicity. Clinical investigation is ongoing.