JCAR014

P1, N=55, Terminated, Fred Hutchinson Cancer Center | Active, not recruiting --> Terminated; Terminated due to slow enrollment and end of funding

While the management of CRS has dramatically improved with the early use of tocilizumab and corticosteroids, how to best predict and treat ICANS remains poorly understood, with up to 30% of patients developing severe ICANS after CD19 CAR T-cell therapy... We retrospectively analyzed data from 195 patients with R/R B-cell malignancies previously treated on a phase I/II clinical trial (NCT01865617) of an investigational defined 1:1 CD8+:CD4+ composition CD19 CAR-T product (JCAR014; training set)...Independent test set included 203 patients treated at our center with the standard-of-care CD19 CAR T-cell products axicabtagene or lisocabatagene maraleucel... We validated the ability of a simple point-of-care index (day +3/day 0 ferritin ratio) to predict the development of severe ICANS after CD19 CAR T-cell therapy in our training and test set. Since serum ferritin levels can be quickly measured by most clinical laboratories, the day +3/day 0 ferritin ratio could become a practical and useful tool for practitioners taking care of CAR T-cell patients. The early identification of patients at high risk of developing severe ICANS days prior to symptoms onset could enable the evaluation of targeted prophylactic interventions in future clinical trials.

Despite the lack of efficacy improvement and similar CAR-T cell kinetics, ongoing durvalumab therapy after JCAR014 was associated with re-expansion of CAR-T cells in blood, late regression of CD19+ and CD19- tumors, and enhanced duration of response. Our results indicate that the timing of initiation of PD-L1 blockade is a key variable that affects outcomes after CD19 CAR-T cell immunotherapy for adults with LBCL.

P1, N=55, Active, not recruiting, Fred Hutchinson Cancer Center | Recruiting --> Active, not recruiting | Trial completion date: Dec 2025 --> Mar 2024 | Trial primary completion date: Dec 2024 --> Mar 2023

All patients received the same lymphodepletion (LD) with cyclophosphamide and fludarabine, followed by JCAR021 infusion...We compared the 15 pts treated at the JCAR021 RP2D with 17 pts treated at the JCAR014 RP2D...At the RP2D, high rates of durable responses were observed. A new cohort including pts in relapse after murine scFv-containing CD19 CAR T cell therapy is currently enrolling.

All patients received lymphodepletion (LD) with cyclophosphamide 300 mg/m2/d and fludarabine 30 mg/m2/d for 3 days, followed by JCAR021 infusion...Consistent with the higher JCAR021 RP2D compared to JCAR014, we observed after JCAR021 better OR (87% versus 59%, respectively), CR rates (67% versus 53%, respectively), and PFS (12-month PFS, 47% versus 25%; CR pts, 64% versus 37%, respectively; Figure B)...At the RP2D, high rates of durable responses were observed. A new cohort with pts in relapse after murine scFv-containing CD19 CAR T cell therapy is currently enrolling.

All pts received lymphodepletion (LD) with cyclophosphamide (Cy) and fludarabine (Flu) followed by JCAR014 infusion. To our knowledge, this is the first report suggesting that PD-L1 blockade may impact toxicity and antitumor response in pts with LBCL undergoing CD19 CAR-T cell therapy. Additional studies will be required to determine the optimal approach for combining CD19 CAR-T cell therapy with PD-1/PD-L1 pathway blockade in LBCL.

To estimate the independent impact of the CAR T-cell product type on outcomes, we retrospectively analyzed data from 129 patients with R/R aggressive B-NHL treated with cyclophosphamide and fludarabine lymphodepletion followed by either a commercially available CD19 CAR T-cell therapy (axicabtagene ciloleucel [axicel] or tisagenlecleucel [tisacel]), or the investigational product JCAR014 on a phase 1/2 clinical trial (NCT01865617). Higher preleukapheresis LDH, largest lesion diameter, and lower ALC were independently associated with lower odds of CR. We conclude that CD19 CAR T-cell product type independently impacts toxicity and efficacy in R/R aggressive B-NHL patients.

P1b, N=30, Terminated, Fred Hutchinson Cancer Center | Trial completion date: Dec 2033 --> May 2021 | Active, not recruiting --> Terminated; Terminated due to slow accrual.

P1, N=78, Recruiting, Fred Hutchinson Cancer Research Center | Trial completion date: Dec 2022 --> Dec 2025 | Trial primary completion date: Dec 2021 --> Dec 2024

P1/2, N=204, Completed, Fred Hutchinson Cancer Research Center | Active, not recruiting --> Completed | Trial completion date: Apr 2034 --> Apr 2021 | Trial primary completion date: Apr 2034 --> Apr 2021

P1b, N=30, Active, not recruiting, Fred Hutchinson Cancer Research Center | Recruiting --> Active, not recruiting | Trial primary completion date: Dec 2021 --> May 2021

Aims To estimate the independent effect of 3 CD19 CAR T-cell products (axicabtagene ciloleucel[axicel], tisagenlecleucel [tisacel], and JCAR014) on CRS and ICANS severity in pts with R/R aggressive NHL. Methods We retrospectively analyzed 136 aggressive NHL pts treated with cyclophosphamide and fludarabine lymphodepletion (LD) followed by CD19 CAR T-cell therapy...We observed higher ICANS severity in older patients treated with axicel; in contrast, age had limited impact on ICANS severity in those receiving tisacel or JCAR014. While further analyses comparing efficacy are warranted, our findings provide insights to guide CAR T-cell product selection in older patients.

Patients received cyclophosphamide and fludarabine lymphodepletion followed by the infusion of axicabtagene ciloleucel (axi-cel; up to 2x108 CAR T cells) or defined-composition CAR T cells (JCAR014; 2x106/kg) on a phase I/II clinical trial (NCT01865617).  While older age was associated with higher risk of severe ICANS after CD19 CAR T-cell therapy, the HCT-CI did not improve CRS or ICANS risk prediction. We plan to validate our findings and refine our models in a larger cohort including other commercial CAR T-cell products. Clinical Trial Registry: NCT01865617

Patients received cyclophosphamide and fludarabine lymphodepletion followed by the infusion of axicabtagene ciloleucel (axi-cel; up to 2x108 CAR T cells) or defined-composition CAR T cells (JCAR014; 2x106/kg) on a phase I/II clinical trial (NCT01865617).  While older age was associated with higher risk of severe ICANS after CD19 CAR T-cell therapy, the HCT-CI did not improve CRS or ICANS risk prediction. We plan to validate our findings and refine our models in a larger cohort including other commercial CAR T-cell products. Clinical Trial Registry: NCT01865617

Patients received cyclophosphamide and fludarabine lymphodepletion followed by the infusion of axicabtagene ciloleucel (axi-cel; up to 2x108 CAR T cells) or defined-composition CAR T cells (JCAR014; 2x106/kg) on a phase I/II clinical trial (NCT01865617).  While older age was associated with higher risk of severe ICANS after CD19 CAR T-cell therapy, the HCT-CI did not improve CRS or ICANS risk prediction. We plan to validate our findings and refine our models in a larger cohort including other commercial CAR T-cell products. Clinical Trial Registry: NCT01865617

Patients received cyclophosphamide and fludarabine lymphodepletion followed by the infusion of axicabtagene ciloleucel (axi-cel; up to 2x108 CAR T cells) or defined-composition CAR T cells (JCAR014; 2x106/kg) on a phase I/II clinical trial (NCT01865617).  While older age was associated with higher risk of severe ICANS after CD19 CAR T-cell therapy, the HCT-CI did not improve CRS or ICANS risk prediction. We plan to validate our findings and refine our models in a larger cohort including other commercial CAR T-cell products. Clinical Trial Registry: NCT01865617

Recent studies in patients with R/R CLL suggest that CD19-directed CAR T cell therapy combined with ibrutinib improves response rates with CTL119 and JCAR014 (Gill et al...Patients received liso-cel infusion at 50 × 106 (dose level [DL]1) or 100 × 106 (DL2) CAR+ T cells after 3 days of lymphodepletion with fludarabine/cyclophosphamide...All patients were R/R to prior ibrutinib; 14 patients (74%) had BTK inhibitor as last prior therapy and 10 (53%) had prior venetoclax...Seven patients (37%) required tocilizumab and/or corticosteroids to manage CRS and/or NEs... Preliminary data show that liso-cel in combination with ibrutinib is associated with manageable safety, including a low incidence of grade 3 CRS and grade ≥3 NEs, and promising efficacy in heavily pretreated patients with R/R CLL/SLL. No clear difference in safety was observed across DLs, and DL2 was selected as the RD for liso-cel in combination with ibrutinib in patients with R/R CLL/SLL. Updated results from the full combination cohort and additional PK/pharmacodynamic data will be reported.

P1, N=66, Recruiting, Fred Hutchinson Cancer Research Center | Trial completion date: Jul 2033 --> Dec 2022 | Trial primary completion date: Dec 2020 --> Dec 2021

P1b, N=42, Recruiting, Fred Hutchinson Cancer Research Center | Trial primary completion date: Dec 2019 --> Dec 2021