Haploidentical mbil-21 Ex Vivo Expanded NK Cells (FC21-NK) for Patients with Multiple Relapsed and Refractory Acute Myeloid Leukemia
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Haploidentical mbil-21 Ex Vivo Expanded NK Cells
(FC21-NK) for Patients with Multiple Relapsed and
Refractory Acute Myeloid Leukemia
Stefan O. Ciurea, Jolie Schafer, Piyanuch Kongtim, Julianne Chen, Doris Soebbing, Kai Cao,
Samer Srour, Elizabeth Shpall, Marina Konopleva, Dean Lee, Richard E. Champlin
1Background
• Relapse/refractory AML has very poor prognosis.
• Retrospective study of 5,500 R/R AML patients treated on large randomized
phase II/III clinical trials in pts with à No improvement in OS over the past 3
decades
• 673 AML pts treated with second salvage at MDACC after year 2000:
– 13% achieved CR/CRp; median duration of CR/CRp – 7.2 mo
– Median OS 4.4 mo, 1 yr OS 16%
• No uniformly accepted treatment of these patients
• Novel approaches are needed
Tchekmedyian R, et al. Blood. 2016
Kantarjian H, et al. Cancer. 2018
2Background
• Natural killer (NK)-cells are a group of lymphocytes capable of recognizing and
eliminating malignant and virally infected cells.
• NK cells have potent anti-leukemic activity but are functionally deficient in AML
• Multiple studies used apheresis collected NK-cells for immunotherapy
• The therapeutic potential has been limited at least in part by the relatively low
number of NK-cells obtained using the apheresis procedure.
Stringaris K, et al. Haematologica. 2014
3Background
• We previously developed an ex vivo NK-cell expansion method based on
K562 feeder cells modified to express membrane bound IL-21 (mbIL-21)
and 4-1BB ligand, (FC21)
– Generated high numbers of hyperfunctional FC21-NK cells
– Enhanced cytotoxicity and cytokine production
• Here we report outcomes of a phase I clinical trial designed to assess the
safety, feasibility and MTD of haploidentical FC21-NK cells for pts with R/R
AML at MDACC
4Methods
Eligibility:
• Relapse/refractory AML patients ≥18 years
• >5% BM/PB blasts
• KPS ≥70 with good organ function
• Patients with relapsed AML after alloSCT were eligible if they had no
active GVHD and did not require immunosuppression.
• Available haploidentical donors; selected based on KIR characteristics,
when multiple donors were available.
5SCHEMA Phase 1 Trial MDACC Expanded Haplo
NK cells + FLAG for R/R AML
Haploidentical donor NK cells; doses – 1x10e6/kg; 1x10e7/kg; 1x10e8/kg
Donor Blood obtained prior to beginning FLAG
G-CSF 5ug/kg/day
Fludarabine 30mg/m2/day
Ara-C 2g/m2/day
NK cell expansion on Cryopreservation (4 hours after Flu)
aAPC x 14d
NK cell infusion
FLAG chemotherapy 0 1 2 3 4 5 6 7 8 9 10 11
5 days (4 if age ≥ 60 y) NK cell therapy
3 days/week x 6 doses
Rest period of 2-14 days
6SCHEMA Phase 1 Trial MDACC Expanded Haplo
NK cells + FLAG FA for R/R AML
Haploidentical donor NK cells; doses – 1x10e6/kg; 1x10e7/kg; 1x10e8/kg
Donor Blood obtained prior to beginning FLAG
G-CSF 5ug/kg/day
Fludarabine 30mg/m2/day
Ara-C 2g/m2/day
NK cell expansion on Cryopreservation (4 hours after Flu)
aAPC x 14d
NK cell infusion
FLAG chemotherapy 0 1 2 3 4 5 6 7 8 9 10 11
5 days (4 if age ≥ 60 y) NK cell therapy
3 days/week x 6 doses
Rest period of 2-14 days Decreased to 2-7 days
7Baseline characteristics
N (total 12) %, range
Age; median (year) 60 25-70 (IQR 36-65)
Sex; male 8 66.7
Therapy-related AML 1 8.3
Secondary/therapy-related AML 5 41.7
Adverse cytogenetic risk 6 50
Adverse ELN 2017 genetic risk 8 66.7
High/very high DRI 12 100
Number of prior treatments, median 5 2-8 (IQR 4-8)
Prior alloSCT 6 50
CNS disease 2 16.67
BM blast count at enrollment; median 47 7-88 (IQR 32-62)
KPS; median 80 70-90 (IQR 70-80)
8Baseline characteristics
N (total 12) %, range
Time from diagnosis to enrollment; median (months) 16.6 2.5-98.1 (IQR 9.72-30.90)
Time from enrollment to NK cell infusion; median (days) 20 10-60 (IQR 18-28)
Pre-infusion chemotherapy
• FLAG 3 25
• FA 9 75
NK cell dose (cell/kg)
• 1x106 8 66.67
• 1x107 4 33.33
NK cell donor
• Sibling 3 25
• Child 8 66.67
• Parent 1 8.33
DSA (N=8) 4 33.33
NK alloreactivity (N=8) 4 50
Allo SCT 5 41.7
Follow up duration for 5 survivors; median (months) 13.02 4.11-42.67 (IQR5.91-15.09)
9Results
• MTD was not reached
• No infusion related toxicity or CRS was observed
• 7 pts had ANC recovery post-NK cell infusion with cumulative incidence of ANC
recovery to 500/mm3 at 60 days 58.3%.
• Responses: 8 pts (66.7%) achieved CR/CRi at 30 days post-NK cell infusion
– CR 4 pts (33.3%), 1 pt had CR with negative MRD
– CRi 4 pts (33.3%)
• 5 pts (41.7%) proceeded to haploidentical SCT from the same donor and were
transplanted in CR/CRi, all but one with persistent MRD.
10Results
• Median follow-up of 13 months (range 4.1-42.7)
• Median OS and PFS were 17.6 and 3.3 months; and 28 and 20 months for pts
receiving alloSCT, respectively
• FC21-NK cells were detected 5-6 weeks after the last NK cell infusion in 2
evaluated pts
Outcomes Whole cohort (n= 12) Pts who underwent AlloSCT (n=5)
Median OS, months 17.6 28
Median PFS, months 3.3 20
2 yr OS, % 31.3 60
2 yr PFS, % 20 30
Relapse at 2 yrs, % 63.3 50
2 yr TRM, % 16.7 20
11OS, PFS, relapse and TRM for the whole cohort
Overall survival B Disease-free survival
1.00
1.00
0.75
0.75
0.50
0.50
0.25
0.25
0.00
0.00
0 10 20 30 40 0 10 20 30 40
Months after transplant Months after transplant
Cumulative incidence of relapse Cumulative incidence of TRM
1
1
.8
.8
.6
.6
.4
.4
.2
.2
0
0
0 10 20 30 40 0 10 20 30 40
Months after transplant Months after transplant
12Disappearance of blast population from the recipient’s
blood and progressive expansion of donor-derived NK cell
population
Blasts
NK cells
13Conclusions
• Infusion of ex vivo expanded haploidentical NK cells in pts with R/R AML is
safe; no infusional reactions or toxicities
• Repeated dosing is possible and likely needed for anti-tumor effect
• High response rate observed in patients with refractory AML to median 5
lines of prior therapy at lower NK cell dose levels
• Responses were observed irrespective of dose.
• Sustained anti-leukemic efficacy was observed in several patients
14Acknowledgement
• Stefan O. Ciurea, MD
• Dean Lee, MD, PhD
• Cell Therapy Lab: Elizabeth Shpall, MD
• HLA lab: Kai Cao, PhD
• Research nurses: Doris Soebbing, Glenda Woodworth
• Data managers: Gabriela Rondon, MD, Julianne Chen
• Grant support: High Impact Clinical Research Support Program (MDACC),
CPRIT, NIH (P01), AML Moonshot Program (MDACC), McKee Family
Foundation, Kiadis Pharma
15THANK YOU
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