Contributions
Abstract: S835
Type: Oral Presentation
Presentation during EHA23: On Saturday, June 16, 2018 from 12:15 - 12:30
Location: Room A8
Background
The prognosis of relapsed/refractory acute lymphoid leukemia (R/R ALL) is very poor, particularly in patients relapsing after allogeneic hematopoietic cell transplantation (alloHCT). New agents, such as inotuzumab or blinatumomab, have improved the complete response rate (CRR) in R/R ALL, but with a progression-free survival (PFS) shorter than 6 months. In the last decade, several chimeric antigen receptor anti-CD19 (CAR19) constructs have been developed. One of them (tisagenlecleucel) was approved by the FDA for pediatric or young adults with R/R ALL. The approval was based on a CRR around 80% with a 6-month PFS around 70%.
Aims
To develop our own academic CAR19 construct for clinical use.
Methods
We selected the anti-CD19 A3B1 hybridoma licensed by our institution, identified the scFv sequence and incorporated the CD8, 4-1BB and CD3z modules next to it. We cloned it into a 3rd generation lentiviral vector and transduced PBMCs from buffy coats after activation with CD3 and CD28 TransACT polymeric nanomatrix (ARI-0001 cells). Once cytotoxicity and specificity were confirmed in vitro and in vivo (in NALM6-xenograft NSG murine models), we scaled-up both lentiviral and cell production, the latter using the CliniMACS Prodigy System (Miltenyi). After reaching all pre-specified acceptance criteria in lymphoaphereses from 3 healthy donors, the Spanish Agency of Medicines approved our IND and also our first pilot clinical trial (clinicaltrials.gov NCT03144583) on May/2017. Eligibility criteria included R/R ALL (adult and pediatric), NHL and CLL who had failed all standard available therapy, but in this abstract we will only report the outcome of patients with R/R ALL.
Results
As of February 2018, we have recruited 8 patients with R/R ALL, all but one relapsing after alloHCT. Median age was 19.5 years (range 3-34) and 50% were female. Patients were included in the trial in first (1), second (5), and third (2) relapse. Two patients were in CR with negative minimal residual disease (MRD) at study inclusion. The median percentage of blasts in bone marrow was 92% (range 73-96%) for the remaining 6 patients. We successfully prepared ARI-0001 cells in all patients, although two patients required two procedures (2/10 [20%] production failure rate globally). After fludarabine (90 mg/m2) and cyclophosphamide (900 mg/m2) chemotherapy, we infused 0.5-5 x106 ARI-0001 cells/kg to 7 patients. In one patient the infusion was delayed due to pneumonitis. Only 4 patients are evaluable at this time (two were in MRD negative CR upon recruitment, one has not been evaluated yet), and all achieved CR with negative MRD (100% CRR) at day +28. Median follow-up is 114 days (range 13-219 days). All 6 patients have developed absolute B-cell aplasia, and none has relapsed so far. Cytokine release syndrome (CRS) has been observed in all 7 patients, but it was of grade III-IV in only one of them (14%). This patient’s grade IV CRS was fully reversible with tocilizumab. Grade I neurotoxicity (confusion and tremor) has been observed in 2 (29%) patients but resolved spontaneously.
Conclusion
It is feasible to prepare CART19 (ARI-0001) cells in a purely academic setting using the automated CliniMACS Prodigy System and home-made lentiviral vectors. The treatment was safe, with only one case (14%) of severe but reversible CRS. The treatment was also efficacious, with a 100% CRR and no relapses so far, although with very limited median follow-up.
Session topic: 26. Gene therapy, cellular immunotherapy and vaccination - Clinical
Keyword(s): Acute lymphoblastic leukemia, CD19, Gene therapy
Abstract: S835
Type: Oral Presentation
Presentation during EHA23: On Saturday, June 16, 2018 from 12:15 - 12:30
Location: Room A8
Background
The prognosis of relapsed/refractory acute lymphoid leukemia (R/R ALL) is very poor, particularly in patients relapsing after allogeneic hematopoietic cell transplantation (alloHCT). New agents, such as inotuzumab or blinatumomab, have improved the complete response rate (CRR) in R/R ALL, but with a progression-free survival (PFS) shorter than 6 months. In the last decade, several chimeric antigen receptor anti-CD19 (CAR19) constructs have been developed. One of them (tisagenlecleucel) was approved by the FDA for pediatric or young adults with R/R ALL. The approval was based on a CRR around 80% with a 6-month PFS around 70%.
Aims
To develop our own academic CAR19 construct for clinical use.
Methods
We selected the anti-CD19 A3B1 hybridoma licensed by our institution, identified the scFv sequence and incorporated the CD8, 4-1BB and CD3z modules next to it. We cloned it into a 3rd generation lentiviral vector and transduced PBMCs from buffy coats after activation with CD3 and CD28 TransACT polymeric nanomatrix (ARI-0001 cells). Once cytotoxicity and specificity were confirmed in vitro and in vivo (in NALM6-xenograft NSG murine models), we scaled-up both lentiviral and cell production, the latter using the CliniMACS Prodigy System (Miltenyi). After reaching all pre-specified acceptance criteria in lymphoaphereses from 3 healthy donors, the Spanish Agency of Medicines approved our IND and also our first pilot clinical trial (clinicaltrials.gov NCT03144583) on May/2017. Eligibility criteria included R/R ALL (adult and pediatric), NHL and CLL who had failed all standard available therapy, but in this abstract we will only report the outcome of patients with R/R ALL.
Results
As of February 2018, we have recruited 8 patients with R/R ALL, all but one relapsing after alloHCT. Median age was 19.5 years (range 3-34) and 50% were female. Patients were included in the trial in first (1), second (5), and third (2) relapse. Two patients were in CR with negative minimal residual disease (MRD) at study inclusion. The median percentage of blasts in bone marrow was 92% (range 73-96%) for the remaining 6 patients. We successfully prepared ARI-0001 cells in all patients, although two patients required two procedures (2/10 [20%] production failure rate globally). After fludarabine (90 mg/m2) and cyclophosphamide (900 mg/m2) chemotherapy, we infused 0.5-5 x106 ARI-0001 cells/kg to 7 patients. In one patient the infusion was delayed due to pneumonitis. Only 4 patients are evaluable at this time (two were in MRD negative CR upon recruitment, one has not been evaluated yet), and all achieved CR with negative MRD (100% CRR) at day +28. Median follow-up is 114 days (range 13-219 days). All 6 patients have developed absolute B-cell aplasia, and none has relapsed so far. Cytokine release syndrome (CRS) has been observed in all 7 patients, but it was of grade III-IV in only one of them (14%). This patient’s grade IV CRS was fully reversible with tocilizumab. Grade I neurotoxicity (confusion and tremor) has been observed in 2 (29%) patients but resolved spontaneously.
Conclusion
It is feasible to prepare CART19 (ARI-0001) cells in a purely academic setting using the automated CliniMACS Prodigy System and home-made lentiviral vectors. The treatment was safe, with only one case (14%) of severe but reversible CRS. The treatment was also efficacious, with a 100% CRR and no relapses so far, although with very limited median follow-up.
Session topic: 26. Gene therapy, cellular immunotherapy and vaccination - Clinical
Keyword(s): Acute lymphoblastic leukemia, CD19, Gene therapy