JCAR014 / Fred Hutchinson Cancer Center, BMS - LARVOL DELTA

Feasibility, Safety and Efficacy of Early Redosing with CD19-Targeted CAR-T Cells in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma (TCT-ASTCT-CIBMTR 2025) - P1/2 | " Patients with R/R B-cell malignancies were enrolled on a phase 1/2 study (NCT01865617) evaluating the safety and efficacy of JCAR014, as previously described (Turtle et al, 2016)... Early CAR T-cell redosing in R/R B-NHL patients was feasible without increased toxicity, and was associated with durable responses (median DOR not reached) lasting beyond 8 years in 5 pts. Despite the absence of repeat LD prior to INF2, we observed CAR T-cell re-expansion after INF2 in 94% of pts and prolonged in vivo CAR T-cell persistence. Acknowledging the limitations of a small sample size, we believe our observations support further studies to investigate the role of early CAR T-cell redosing."

CAR T-Cell Therapy • Clinical • B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Improving the ICAHT grading criteria using time-series clustering. (ASCO 2024) - "The most common CAR T-cell products were the investigational CD19 CAR T-cell product JCAR014 (n = 197; 33%), axi-cel (n = 129; 21%), and liso-cel (n = 73; 12%). Unsupervised time-series clustering identified patterns of ANC recovery not captured by the ICAHT grading system and more strongly associated with OS than ICAHT grades. Incorporating these distinct patterns of recovery into a modified ICAHT grading system improved predictions of OS compared to the original ICAHT grades."

Hematological Disorders • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Predictors of severe hematotoxicity after CAR T-cell therapy. (ASCO 2024) - "The most common CAR T-cell products were the investigational CD19 CAR T-cell product JCAR014 (n = 197; 33%), axicabtagene ciloleucel (n = 129; 21%), and lisocabtagene maraleucel (n = 73; 12%). We identified pre- and post-infusion predictors of grade 3-4 ICAHT and internally validated a multivariable logistic regression model including disease-type, pre-LD ANC, pre-LD LDH, peak CRP, peak ferritin, and CRS grade. We plan to further evaluate our model in an external cohort."

CAR T-Cell Therapy • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Indolent Lymphoma • Leukemia • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology

huJCAR014 CAR-T Cells in Treating Adult Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma or Acute Lymphoblastic Leukemia (clinicaltrials.gov) - P1 | N=55 | Terminated | Sponsor: Fred Hutchinson Cancer Center | Active, not recruiting ➔ Terminated; Terminated due to slow enrollment and end of funding

CAR T-Cell Therapy • Trial termination • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Acute Lymphoblastic Leukemia • BCL2 • BCL6 • CD19 • CD4 • IL6 • SELL

CAR T-cell Therapy Shows 6-Year Durability in CLL Patients (Managed Healthcare Executive) - P1/2 | N=204 | NCT01865617 | "In the phase 1/2 study (NCT01865617), 49 patients received JCAR014, a novel CAR T-cell therapy, with (n = 19) or without (n = 30) concurrent ibrutinib (Imbruvica). At a median follow-up of 79.6 months (IQR, 60.5-87.5), the median progression-free survival (PFS) for all patients who received CAR T-cell therapy was 8.9 months (95% CI, 3.0-19.9), and the median overall survival (OS) was 25.0 months (95% CI, 11.5-62.1). The 6-year PFS rate was 17.8% (95% CI, 9.7%-32.8%), and the 6-year OS rate was 31.2% (95% CI, 20.3%-48.1%). The median duration of response (DOR) was 18.9 months (95% CI, 9.66-55.6) with a 6-year DOR estimate of 26.4% (95% CI, 14.8%-47.2%)...The median patient age was 61 years (IQR, 55-67), and 94% of patients (n = 46) had high risk cytogenic profiles, including a complex karyotype or 17p deletion...Cytokine release syndrome (CRS) was reported in 40 patients (82%), with 7 patients (14%) experiencing grade 3 or higher CRS."

P1/2 data • Chronic Lymphocytic Leukemia

Early Prediction of Severe Icans after CD19 CAR T-Cell Therapy Based on Serum Ferritin Levels (TCT-ASTCT-CIBMTR 2024) - "Serum ferritin levels on day +3 are strongly associated with severe ICANS after CD19 CAR T-cell therapy with axi-cel and liso-cel, and was validated in an external cohort including clinical trial patients treated with JCAR014. Validated predictive models using point-of-care assessments create an opportunity to identify high-risk patients who could benefit from early or prophylactic interventions."

CAR T-Cell Therapy • IO biomarker • Acute Lymphocytic Leukemia • Chronic Lymphocytic Leukemia • Hematological Malignancies • Immunology • Leukemia • Lymphoma • Oncology • Rare Diseases

Day +3/Day 0 Ferritin Ratio: A Simple Point-of-Care Index Predictive of Severe Immune Effector Cell-Associated Neurotoxicity Syndrome after CD19 CAR T-Cell Therapy (ASH 2023) - P1/2 | "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..."

CAR T-Cell Therapy • Acute Lymphocytic Leukemia • Chronic Lymphocytic Leukemia • Hematological Malignancies • Immunology • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Rare Diseases • CD4 • CD8 • IL2 • IL2RA

CAR T-Cell Therapy Can Keep Subset of CLL Patients Progression-Free for 6 Years (Cancer Therapy Advisor) - P1/2 | N=204 | NCT01865617 | "CD19-targeted chimeric antigen receptor (CAR) T-cell therapy, given with or without ibrutinib, can produce lasting remissions in patients with relapsed or refractory chronic lymphocytic leukemia...The data, from a phase 1/2 trial of heavily pretreated patients, showed that 18% were alive and progression-free at 6 years...patients received lymphodepleting chemotherapy followed by an infusion of JCAR014 (2 × 105, 2 × 106, or 2 × 107 CD19 CAR-T cells/kg). Nineteen patients received concurrent ibrutinib, and 30 did not...Forty-seven patients were evaluable for response. At a median follow-up of 79.6 months, the median duration of response was 18.9 months....In all 49 patients, the median progression-free survival (PFS) was 8.9 months, and the median overall survival (OS) was 25.0 months. The 6-year PFS rate was 17.8%, and the 6-year OS rate was 31.2%."

P1/2 data • Chronic Lymphocytic Leukemia

Timing of Anti-PD-L1 Antibody Initiation Affects Efficacy/Toxicity of CD19 CAR-T Cell Therapy for Large B-Cell Lymphoma. (PubMed, Blood Adv) - "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."

CAR T-Cell Therapy • Journal • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Immunology • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • PD-1

CD19 CAR T Cell Therapy Yield High MRD-Negativity in R/R (Cancer Network) - P1/2 | N=204 | NCT01865617 | "...JCAR014 produced durable measurable residual disease (MRD)–negative responses in patients with pretreated, high-risk, ibrutinib (Imbruvica)–refractory relapsed or refractory chronic lymphocytic leukemia (CLL), according to 5-year follow-up findings from a phase 1/2 trial...With a median follow-up of 79.6 months (interquartile range [IQR], 60.5-87.5), the median duration of response (DOR) was 18.9 months (95% CI, 9.7-55.6) in those with a complete response (CR), incomplete CR (CRi), or partial response...at day 28 assessment (n = 33). Additionally, 26% (95% CI, 15%-47%) of patients had ongoing responses at 6 years....The median progression-free survival (PFS) was 8.9 months (95% CI, 3.0-19.9), and the 6-year PFS rate was 18% (95% CI, 10%-33%) in all infused patients (n = 49). The median overall survival (OS) in this population was 25.0 months (95% CI, 11.5-62.1), and the 6-year OS rate was 31% (95% CI, 20%-48%)."

P1/2 data • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology

huJCAR014 CAR-T Cells in Treating Adult Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma or Acute Lymphoblastic Leukemia (clinicaltrials.gov) - P1 | N=55 | Active, not recruiting | Sponsor: Fred Hutchinson Cancer Center | Recruiting ➔ Active, not recruiting | Trial completion date: Dec 2025 ➔ Mar 2024 | Trial primary completion date: Dec 2024 ➔ Mar 2023

CAR T-Cell Therapy • Enrollment closed • Trial completion date • Trial primary completion date • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Acute Lymphoblastic Leukemia • BCL2 • BCL6 • CD19 • CD4 • CD8

Impact of CD19 CAR T-cell product type on outcomes in relapsed or refractory aggressive B-NHL. (PubMed, Blood) - P1/2 | "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 I/II 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."

CAR T-Cell Therapy • Journal • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD19

CAR T-Cell Therapy for Relapsed or Refractory Large B-Cell Lymphoma Using a Fully Human CD19-Targeted Single Chain Variable Fragment: Results of a First-in-Human Phase I/II Study (ASH 2022) - P1, P1/2 | "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."

CAR T-Cell Therapy • IO biomarker • P1/2 data • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Inflammation • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Transplantation • CD19 • CD8

Timing of PD-L1 Blockade with Durvalumab May Affect Outcomes of CD19 CAR-T Cell Therapy for Relapsed/Refractory Large B-Cell Lymphoma (ASH 2022) - P1/2, P1b | "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."

CAR T-Cell Therapy • IO biomarker • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Inflammation • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • CD19

Fully Human CD19-Targeted CAR T-Cell Therapy for Relapsed or Refractory Large B-Cell Lymphoma: Results of a First-in-Human Phase I/II Study (TCT-ASTCT-CIBMTR 2023) - P1, P1/2 | "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."

CAR T-Cell Therapy • P1/2 data • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD19 • CD8

[VIRTUAL] CRS AND ICANS RISK ACROSS THREE CD19 CAR-T CELL PRODUCTS IN PATIENTS WITH AGGRESSIVE NHL (EHA 2021) - P1/2 | "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."

CAR T-Cell Therapy • Clinical • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Immune Modulation • Inflammation • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Transplantation • CD19

Comparison of Efficacy and Toxicity of CD19-Specific Chimeric Antigen Receptor T-Cells Alone or in Combination with Ibrutinib for Relapsed and/or Refractory CLL (ASH 2018) - P1/2; "Methods We conducted a phase 1/2 study of CD19 CAR-T cell immunotherapy in R/R CLL pts and established a regimen of cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion followed by JCAR014 at 2 x 106 CAR-T cells/kg (Turtle, JCO 2017). Conclusion Administration of ibrutinib from 2 weeks before leukapheresis until 3 months after JCAR014 was well tolerated in most pts. This approach might decrease the incidence of severe CRS and improve responses in pts with R/R CLL."

CAR T-Cell Therapy • Clinical • Combination therapy • Biosimilar • Cardiovascular • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Indolent Lymphoma • Leukemia • Mood Disorders • Non-Hodgkin’s Lymphoma • Oncology

[VIRTUAL] Transcend CLL 004: Phase 1 Cohort of Lisocabtagene Maraleucel (liso-cel) in Combination with Ibrutinib for Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) (ASH 2020) - P1/2 | "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...."

Clinical • Combination therapy • P1 data • Atrial Fibrillation • Cardiovascular • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Hypertension • Infectious Disease • Leukemia • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Respiratory Diseases • Small Lymphocytic Lymphoma • CD8 • TP53

"Hold your horses - haven’t looked at Breyanzi yet (JCAR014 ≠ JCAR017) 😉" (@drjgauthier)

JCAR014 and Durvalumab in Treating Patients With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma (clinicaltrials.gov) - P1b | N=30 | Terminated | Sponsor: Fred Hutchinson Cancer Center | Trial completion date: Dec 2033 ➔ May 2021 | Active, not recruiting ➔ Terminated; Terminated due to slow accrual.

Combination therapy • Trial completion date • Trial termination • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • BCL6 • CD19

"Thx for posting NCT#, I suspected this was JCAR014" (@DrPaulyDeSantis)

huJCAR014 CAR-T Cells in Treating Adult Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma or Acute Lymphoblastic Leukemia (clinicaltrials.gov) - P1; N=78; Recruiting; Sponsor: Fred Hutchinson Cancer Research Center; Trial completion date: Dec 2022 ➔ Dec 2025; Trial primary completion date: Dec 2021 ➔ Dec 2024

CAR T-Cell Therapy • Clinical • Trial completion date • Trial primary completion date • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Acute Lymphoblastic Leukemia • BCL2 • BCL6 • CD19 • CD4 • CD8 • MRI • PCR

Efficacy and Toxicity of JCAR014 in Combination with Durvalumab for the Treatment of Patients with Relapsed/Refractory Aggressive B-Cell Non-Hodgkin Lymphoma (ASH 2018) - P1b; "All pts receive lymphodepletion chemotherapy with cyclophosphamide and fludarabine followed by infusion of JCAR014. Conclusion The combination of JCAR014 with durvalumab for the treatment of adult pts with aggressive B-cell NHL appears safe; however, dose escalation is ongoing. Complete responses were observed both at initial restaging after JCAR014 infusion, and also subsequently in pts continuing durvalumab therapy after initially failing to achieve CR."

Clinical • Combination therapy • PD(L)-1 Biomarker • Biosimilar • Hematological Disorders • Hematological Malignancies • Immune Modulation • Immunology • Inflammation • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

[VIRTUAL] CD19 CAR T-cell product type independently impacts CRS and ICANS severity in patients with aggressive NHL. (ASCO 2021) - P1/2 | "Thus, we assessed the independent impact of 3 CD19 CAR T-cell products (axicabtagene ciloleucel[axicel], tisagenlecleucel [tisacel], and JCAR014) on CRS and ICANS severity in 136 pts with R/R aggressive NHL . We retrospectively analyzed aggressive NHL pts treated at our institutions with cyclophosphamide and fludarabine lymphodepletion (LD) followed by CD19 CAR T-cell therapy... CAR T-cell product type independently impacts CRS and ICANS severity in NHL pts . Our findings provide key insights to guide patient and CAR T-cell product selection."

CAR T-Cell Therapy • Clinical • Hematological Malignancies • Immune Modulation • Inflammation • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Transplantation • CD19

RG9213011: Laboratory Treated T Cells in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia, Non-Hodgkin Lymphoma, or Acute Lymphoblastic Leukemia (clinicaltrials.gov) - P1/2; N=204; Completed; Sponsor: Fred Hutchinson Cancer Research Center; Active, not recruiting ➔ Completed; Trial completion date: Apr 2034 ➔ Apr 2021; Trial primary completion date: Apr 2034 ➔ Apr 2021

Clinical • Trial completion • Trial completion date • Trial primary completion date • Acute Lymphocytic Leukemia • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Indolent Lymphoma • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • T Acute Lymphoblastic Leukemia • CD19