WZTL-002

WZTL-002 CAR T-cells were administered intravenously after 3 days of fludarabine (30mg/m2/day) and cyclophosphamide (500mg/m2/day) lymphodepletion...Grade 1 – 2 CRS occurred in 13 patients (62%); 6 received tocilizumab and 3 dexamethasone... In this dose escalation trial of a novel third-generation CD19-directed CAR T-cell product that combines CD28 and TLR2 co-stimulatory domains for r/r B-NHL, we observed no severe CRS, no ICANS of any grade and complete responses at all dose levels. At RP2D, in vivo CAR T-cell expansion was similar to or greater than other CD19-directed products. In conjunction with preclinical findings, this study suggests interposition of a TLR2 domain between CD28 and CD3ζ domains may reduce CAR T-cell-related ICANS risk while retaining efficacy.

P1, N=30, Recruiting, Malaghan Institute of Medical Research | N=12 --> 30 | Trial completion date: Aug 2026 --> Feb 2029 | Trial primary completion date: Sep 2021 --> May 2024

Registry data indicate a CD28-costimulated anti-CD19 CAR T-cell product (axi-cel, 1928z) results in higher response rates, but more frequent neurotoxicity and severe cytokine release syndrome (CRS), than a 41BB-costimulated product (tisa-cel, 19BBz)...Following fludarabine and cyclophosphamide lymphodepletion, 5 × 10e4/kg to 1 × 10e6/kg autologous 1928T2z CAR T-cells were administered to 20 patients with relapsed or refractory B-cell non-Hodgkin lymphomas...Preliminary phase 1 clinical trial findings suggest third-generation 1928T2z CAR T-cells combine a low incidence of severe CRS and neurotoxicity with encouraging efficacy and robust expansion at low dose. Clinical investigation of 1928T2z CAR T-cells is ongoing.

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.