Phase I trial of expanded, activated autologous NK-cell infusions with trastuzumab in patients with HER2-positive cancers

Soo Chin Lee, Noriko Shimasaki, Joline S.J. Lim, Andrea Wong, Kritika Yadav, Wei Peng Yong, Lip Kun Tan, Liang Piu Koh, Michelle L.M. Poon, Sing Huang Tan, Samuel G.W. Ow, Lavina Bharwani, Yoon Sim Yap, Mabel Z.Q. Foo, Elaine Coustan-Smith, Raghav Sundar, Hon Lyn Tan, Wan Qin Chong, Nesaretnam Barr Kumarakulasinghe, Jedidah L.M. LieowPriscillia J.X. Koe, Boon Cher Goh, Dario Campana

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4494-4502
Number of pages9
JournalClinical Cancer Research
Volume26
Issue number17
DOIs
StatePublished - Sep 2020
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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