Quadruple gene-engineered natural killer cells enable multi-antigen targeting for durable antitumor activity against multiple myeloma

被引：56

作者：

Cichocki, Frank ^{[1
]}

Bjordahl, Ryan ^{[2
]}

Goodridge, Jodie P. ^{[2
]}

Mahmood, Sajid ^{[2
]}

Gaidarova, Svetlana ^{[2
]}

Abujarour, Ramzey ^{[1
]}

Davis, Zachary B. ^{[1
]}

Merino, Aimee ^{[1
]}

Tuininga, Katie ^{[1
]}

Wang, Hongbo ^{[1
]}

Kumar, Akhilesh ^{[1
]}

Groff, Brian ^{[2
]}

Witty, Alec ^{[2
]}

Bonello, Greg ^{[2
]}

Huffman, Janel ^{[2
]}

Dailey, Thomas ^{[2
]}

Lee, Tom T. ^{[2
]}

Malmberg, Karl-Johan ^{[3
]}

Walcheck, Bruce ^{[4
]}

Hoepken, Uta ^{[5
]}

Rehm, Armin ^{[5
]}

Valamehr, Bahram ^{[2
]}

Miller, Jeffrey S. ^{[1
]}

机构：

[1] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA

[2] Fate Therapeut, San Diego, CA 92121 USA

[3] Oslo Univ Hosp, Oslo, Norway

[4] Univ Minnesota, Dept Vet & Biomed Sci, St Paul, MN 55108 USA

[5] Max Delbruck Ctr Mol Med, MDC, Berlin, Germany

来源：

NATURE COMMUNICATIONS | 2022年 / 13卷 / 01期

关键词：

MATURATION ANTIGEN; NK CELLS; T-CELLS; THERAPY; TRANSPLANTATION; DARATUMUMAB; EXPANSION;

D O I：

10.1038/s41467-022-35127-2

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Allogeneic natural killer (NK) cell adoptive transfer is a promising treatment for several cancers but is less effective for the treatment of multiple myeloma. In this study, we report on quadruple gene-engineered induced pluripotent stem cell (iPSC)-derived NK cells designed for mass production from a renewable source and for dual targeting against multiple myeloma through the introduction of an NK cell-optimized chimeric antigen receptor (CAR) specific for B cell maturation antigen (BCMA) and a high affinity, non-cleavable CD16 to augment antibody-dependent cellular cytotoxicity when combined with therapeutic anti-CD38 antibodies. Additionally, these cells express a membrane-bound interleukin-15 fusion molecule to enhance function and persistence along with knock out of CD38 to prevent antibody-mediated fratricide and enhance NK cell metabolic fitness. In various preclinical models, including xenogeneic adoptive transfer models, quadruple gene-engineered NK cells consistently demonstrate durable antitumor activity independent of exogenous cytokine support. Results presented here support clinical translation of this off-the-shelf strategy for effective treatment of multiple myeloma. The use of chimeric antigen receptor modified immune cell therapeutics has improved the treatment of a range of tumours. Here the authors explore a dual-target iPSC-derived NK cell product as a potential therapeutic for the treatment of multiple myeloma.

引用

页数：15

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