TY - JOUR
T1 - A Phase 1 Trial of CNDO-109–Activated Natural Killer Cells in Patients with High-Risk Acute Myeloid Leukemia
AU - Fehniger, Todd A.
AU - Miller, Jeffrey S.
AU - Stuart, Robert K.
AU - Cooley, Sarah
AU - Salhotra, Amandeep
AU - Curtsinger, Julie
AU - Westervelt, Peter
AU - DiPersio, John F.
AU - Hillman, Timothy M.
AU - Silver, Nova
AU - Szarek, Michael
AU - Gorelik, Leonid
AU - Lowdell, Mark W.
AU - Rowinsky, Eric
N1 - Publisher Copyright:
© 2018 The American Society for Blood and Marrow Transplantation
PY - 2018/8
Y1 - 2018/8
N2 - Natural killer (NK) cells are an emerging immunotherapy approach to acute myeloid leukemia (AML); however, the optimal approach to activate NK cells before adoptive transfer remains unclear. Human NK cells that are primed with the CTV-1 leukemia cell line lysate CNDO-109 exhibit enhanced cytotoxicity against NK cell–resistant cell lines. To translate this finding to the clinic, CNDO-109–activated NK cells (CNDO-109-NK cells) isolated from related HLA-haploidentical donors were evaluated in a phase 1 dose-escalation trial at doses of 3 × 105 (n = 3), 1 × 106 (n = 3), and 3 × 106 (n = 6) cells/kg in patients with AML in first complete remission (CR1) at high risk for recurrence. Before CNDO-109-NK cell administration, patients were treated with lymphodepleting fludarabine/cyclophosphamide. CNDO-109-NK cells were well tolerated, and no dose-limiting toxicities were observed at the highest tested dose. The median relapse-free survival (RFS) by dose level was 105 (3 × 105), 156 (1 × 106), and 337 (3 × 106) days. Two patients remained relapse-free in post-trial follow-up, with RFS durations exceeding 42.5 months. Donor NK cell microchimerism was detected on day 7 in 10 of 12 patients, with 3 patients having evidence of donor cells on day 14 or later. This trial establishes that CNDO-109-NK cells generated from related HLA haploidentical donors, cryopreserved, and then safely administered to AML patients with transient persistence without exogenous cytokine support. Three durable complete remissions of 32.6 to 47.6+ months were observed, suggesting additional clinical investigation of CNDO-109-NK cells for patients with myeloid malignancies, alone or in combination with additional immunotherapy strategies, is warranted.
AB - Natural killer (NK) cells are an emerging immunotherapy approach to acute myeloid leukemia (AML); however, the optimal approach to activate NK cells before adoptive transfer remains unclear. Human NK cells that are primed with the CTV-1 leukemia cell line lysate CNDO-109 exhibit enhanced cytotoxicity against NK cell–resistant cell lines. To translate this finding to the clinic, CNDO-109–activated NK cells (CNDO-109-NK cells) isolated from related HLA-haploidentical donors were evaluated in a phase 1 dose-escalation trial at doses of 3 × 105 (n = 3), 1 × 106 (n = 3), and 3 × 106 (n = 6) cells/kg in patients with AML in first complete remission (CR1) at high risk for recurrence. Before CNDO-109-NK cell administration, patients were treated with lymphodepleting fludarabine/cyclophosphamide. CNDO-109-NK cells were well tolerated, and no dose-limiting toxicities were observed at the highest tested dose. The median relapse-free survival (RFS) by dose level was 105 (3 × 105), 156 (1 × 106), and 337 (3 × 106) days. Two patients remained relapse-free in post-trial follow-up, with RFS durations exceeding 42.5 months. Donor NK cell microchimerism was detected on day 7 in 10 of 12 patients, with 3 patients having evidence of donor cells on day 14 or later. This trial establishes that CNDO-109-NK cells generated from related HLA haploidentical donors, cryopreserved, and then safely administered to AML patients with transient persistence without exogenous cytokine support. Three durable complete remissions of 32.6 to 47.6+ months were observed, suggesting additional clinical investigation of CNDO-109-NK cells for patients with myeloid malignancies, alone or in combination with additional immunotherapy strategies, is warranted.
KW - Acute myeloid leukemia
KW - CNDO-109–activated natural killer cells
UR - http://www.scopus.com/inward/record.url?scp=85046167070&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85046167070&partnerID=8YFLogxK
U2 - 10.1016/j.bbmt.2018.03.019
DO - 10.1016/j.bbmt.2018.03.019
M3 - Article
C2 - 29597002
AN - SCOPUS:85046167070
SN - 1083-8791
VL - 24
SP - 1581
EP - 1589
JO - Biology of Blood and Marrow Transplantation
JF - Biology of Blood and Marrow Transplantation
IS - 8
ER -
