Anti-NKG2C/IL-15/anti-CD33 killer engager directs primary and iPSC-derived NKG2C + NK cells to target myeloid leukemia.

Emily Chiu, Martin Felices, Frank Cichocki, Zachary Davis, Hongbo Wang, Katie Tuninga, Daniel A. Vallera, Tom Lee, Ryan Bjordahl, Karl Johan Malmberg, Bahram Valamehr, Jeffrey S. Miller

Research output: Contribution to journalArticlepeer-review

Abstract

Natural killer (NK) cells mediate the cytolysis of transformed cells and are currently used as an adoptive cellular therapy to treat cancer. Infection with human cytomegalovirus has been shown to expand a subset of “adaptive” NK cells expressing the activation receptor NKG2C that have preferred functional attributes distinct from conventional NK cells. Because NKG2C delivers a strong activating signal to NK cells, we hypothesized that NKG2C could specifically trigger NK-cell-mediated antitumor responses. To elicit a tumor-directed response from NKG2C+ NK cells, we created an anti-NKG2C/IL-15/anti-CD33 killer engager called NKG2C-KE that directs NKG2C+ cells to target CD33+ cells and tumor-associated antigen expressed by acute myelogenous leukemia cells. The NKG2C-KE induced specific degranulation, interferon-γ production, and proliferation of NKG2C-expressing NK cells from patients who reactivated cytomegalovirus after allogeneic transplantation. The NKG2C-KE was also tested in a more homogeneous system using induced pluripotent stem cell (iPSC)-derived NK (iNK) cells that have been engineered to express NKG2C at high levels. The NKG2C-KE triggered iNK-cell-mediated cytotoxicity against CD33+ cells and primary AML blasts. The NKG2C-KE-specific interaction with adaptive NK and NKG2C+ iNK cells represents a new immunotherapeutic paradigm that uniquely engages highly active NK cells to induce cytotoxicity against AML through redirected targeting.

Original languageEnglish (US)
JournalMolecular Therapy
Early online dateJun 24 2021
DOIs
StateE-pub ahead of print - Jun 24 2021

Bibliographical note

Funding Information:
We would like to acknowledge the Flow Cytometry Core and Translational Therapy Laboratory. This work was supported by NIH grants NCI F30-CA232481-01A1 (to E.C.) NCI P01 CA111412 (to J.S.M., D.A.V., and M.F.), NCI P01 65493 (to J.S.M.), R35 CA197292 (to J.S.M.), P30 CA077598 (to J.S.M. and M.F.), US Department of Defense grant CA150085 (to M.F.), the Minnesota Masonic Charities , and the Killebrew-Thompson Memorial Fund . T.L., R.B., and B.V. are employees of Fate Therapeutics and directly contributed to this manuscript. F.C., K.J.M., and J.S.M. earn income from and hold stock in Fate Therapeutics , who partially funded the iPSC-derived NK cell component of this work. These conflicts have been reviewed and managed by the University of Minnesota (and Oslo University, for K.J.M.) in accordance with their conflict of interest policies.

Funding Information:
We would like to acknowledge the Flow Cytometry Core and Translational Therapy Laboratory. This work was supported by NIH grants NCI F30-CA232481-01A1 (to E.C.) NCI P01 CA111412 (to J.S.M. D.A.V. and M.F.), NCI P01 65493 (to J.S.M.), R35 CA197292 (to J.S.M.), P30 CA077598 (to J.S.M. and M.F.), US Department of Defense grant CA150085 (to M.F.), the Minnesota Masonic Charities, and the Killebrew-Thompson Memorial Fund. T.L. R.B. and B.V. are employees of Fate Therapeutics and directly contributed to this manuscript. F.C. K.J.M. and J.S.M. earn income from and hold stock in Fate Therapeutics, who partially funded the iPSC-derived NK cell component of this work. These conflicts have been reviewed and managed by the University of Minnesota (and Oslo University, for K.J.M.) in accordance with their conflict of interest policies. Conceptualization, E.C. M.F. F.C. and J.S.M.; methodology, M.F. F.C. R.B. B.V. and J.S.M.; investigation, E.C.; resources, Z.D. H.W. K.T. T.L. and R.B.; writing ? original draft, E.C. and Z.D.; writing ? review & editing, M.F. F.C. Z.D. D.A.V. and J.S.M.; visualization, E.C.; supervision, M.F. F.C. D.A.V. K.J.M. and J.S.M.

Publisher Copyright:
© 2021 The American Society of Gene and Cell Therapy

Keywords

  • acute myeloid leukemia
  • adoptive transfer
  • immunotherapy
  • iNK
  • killer engager
  • natural killer cell
  • NK cells
  • NKG2C

PubMed: MeSH publication types

  • Journal Article

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