TY - JOUR
T1 - Phase I trial of expanded, activated autologous NK-cell infusions with trastuzumab in patients with HER2-positive cancers
AU - Lee, Soo Chin
AU - Shimasaki, Noriko
AU - Lim, Joline S.J.
AU - Wong, Andrea
AU - Yadav, Kritika
AU - Yong, Wei Peng
AU - Tan, Lip Kun
AU - Koh, Liang Piu
AU - Poon, Michelle L.M.
AU - Tan, Sing Huang
AU - Ow, Samuel G.W.
AU - Bharwani, Lavina
AU - Yap, Yoon Sim
AU - Foo, Mabel Z.Q.
AU - Coustan-Smith, Elaine
AU - Sundar, Raghav
AU - Tan, Hon Lyn
AU - Chong, Wan Qin
AU - Kumarakulasinghe, Nesaretnam Barr
AU - Lieow, Jedidah L.M.
AU - Koe, Priscillia J.X.
AU - Goh, Boon Cher
AU - Campana, Dario
N1 - Funding Information:
We thank Sally Chai, Liza Ho, Michelle Ng, Hilary Mock, Huai Hui Wong, Lee Hui Chua, Wan Rong Sia, and Miki Wong for expert assistance in the preparation of NK cells for infusion. This study was supported by the National Medical Research Council, Singapore (NMRC/CSA/015/2009, NMRC/CSA-SI/0004/2015, NMRC/ CG/012/2013, NMRC/CG/M005/2017_NCIS, NMRC/STaR/0025/2015).
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/9
Y1 - 2020/9
N2 - Purpose: Natural killer (NK) cells exert antibody-dependent cell cytotoxicity (ADCC). We infused expanded, activated autologous NK cells to potentiate trastuzumab-mediated ADCC in patients with HER2-positive malignancies. Patients and Methods: In a phase I trial, patients with treatment-refractory HER2-positive solid tumors received trastuzumab, with or without bevacizumab, and autologous NK cells expanded by 10-day coculture with K562-mb15-41BBL cells. Primary objectives included safety and recommended phase II dose determination; secondary objectives included monitoring NK-cell activity and RECIST antitumor efficacy. Results: In 60 cultures with cells from 31 subjects, median NK-cell expansion from peripheral blood was 340-fold (range, 91-603). NK cells expressed high levels of CD16, the mediator of ADCC, and exerted powerful killing of trastuzumab-targeted cells. In the 22 subjects enrolled in phase I dose escalation, trastuzumab plus NK cells were well tolerated; MTD was not reached. Phase IB (n ¼ 9) included multiple cycles of NK cells (1 * 107/kg) and addition of bevacizumab. Although no objective response was observed, 6 of 19 subjects who received at least 1 * 107/kg NK cells at cycle 1 had stable disease for ≥6 months (median, 8.8 months; range 6.0-12.0). One patient, the only one with the high-affinity F158V CD16 variant, had a partial response. Peripheral blood NK cells progressively downregulated CD16 postinfusion; paired tumor biopsies showed increased NK cells, lymphocytic infiltrates, and apoptosis posttreatment. Conclusions: NK-cell therapy in combination with trastuzumab was well tolerated, with target engagement and preliminary antitumor activity, supporting continued assessment of this approach in phase II trials.
AB - Purpose: Natural killer (NK) cells exert antibody-dependent cell cytotoxicity (ADCC). We infused expanded, activated autologous NK cells to potentiate trastuzumab-mediated ADCC in patients with HER2-positive malignancies. Patients and Methods: In a phase I trial, patients with treatment-refractory HER2-positive solid tumors received trastuzumab, with or without bevacizumab, and autologous NK cells expanded by 10-day coculture with K562-mb15-41BBL cells. Primary objectives included safety and recommended phase II dose determination; secondary objectives included monitoring NK-cell activity and RECIST antitumor efficacy. Results: In 60 cultures with cells from 31 subjects, median NK-cell expansion from peripheral blood was 340-fold (range, 91-603). NK cells expressed high levels of CD16, the mediator of ADCC, and exerted powerful killing of trastuzumab-targeted cells. In the 22 subjects enrolled in phase I dose escalation, trastuzumab plus NK cells were well tolerated; MTD was not reached. Phase IB (n ¼ 9) included multiple cycles of NK cells (1 * 107/kg) and addition of bevacizumab. Although no objective response was observed, 6 of 19 subjects who received at least 1 * 107/kg NK cells at cycle 1 had stable disease for ≥6 months (median, 8.8 months; range 6.0-12.0). One patient, the only one with the high-affinity F158V CD16 variant, had a partial response. Peripheral blood NK cells progressively downregulated CD16 postinfusion; paired tumor biopsies showed increased NK cells, lymphocytic infiltrates, and apoptosis posttreatment. Conclusions: NK-cell therapy in combination with trastuzumab was well tolerated, with target engagement and preliminary antitumor activity, supporting continued assessment of this approach in phase II trials.
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U2 - 10.1158/1078-0432.CCR-20-0768
DO - 10.1158/1078-0432.CCR-20-0768
M3 - Article
C2 - 32522887
AN - SCOPUS:85094905891
SN - 1078-0432
VL - 26
SP - 4494
EP - 4502
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 17
ER -