Open AccessCD38‐specific Chimeric Antigen Receptor Expressing Natural Killer KHYG‐1 Cells: A Proof of Concept for an “Off the Shelf” Therapy for Multiple Myeloma
Author(s) -
Stikvoort Arwen,
Schans Jort,
Sarkar Subhashis,
Poels Renée,
Ruiter Ruud,
Naik Jyoti,
Yuan Huipin,
Bruijn Joost D.,
Donk Niels W. C. J.,
Zweegman Sonja,
Themeli Maria,
Groen Richard,
O'Dwyer Michael,
Mutis Tuna
Publication year - 2021
Publication title -
hemasphere
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.677
H-Index - 11
ISSN - 2572-9241
DOI - 10.1097/hs9.0000000000000596
Subject(s) - cd38 , chimeric antigen receptor , daratumumab , cancer research , antigen , haematopoiesis , bone marrow , cytotoxic t cell , cell therapy , immune system , immunotherapy , stem cell , immunology , chemistry , antibody , biology , monoclonal antibody , in vitro , microbiology and biotechnology , cd34 , biochemistry
Chimeric antigen receptor (CAR) T cells are highly successful in the treatment of hematologic malignancies. We recently generated affinity‐optimized CD38CAR T cells, which effectively eliminate multiple myeloma (MM) cells with little or no toxicities against nonmalignant hematopoietic cells. The lack of universal donors and long manufacturing times however limit the broad application of CAR T cell therapies. Natural killer (NK) cells generated from third party individuals may represent a viable source of “off the shelf” CAR‐based products, as they are not associated with graft‐versus‐host disease unlike allogeneic T cells. We therefore explored the preclinical anti‐MM efficacy and potential toxicity of the CD38CAR NK concept by expressing affinity‐optimized CD38CARs in KHYG‐1 cells, an immortal NK cell line with excellent expansion properties. KHYG‐1 cells retrovirally transduced with the affinity‐optimized CD38CARs expanded vigorously and mediated effective CD38‐dependent cytotoxicity towards CD38 high MM cell lines as well as primary MM cells ex vivo. Importantly, the intermediate affinity CD38CAR transduced KHYG‐1 cells spared CD38 neg or CD38 int nonmalignant hematopoietic cells, indicating an optimal tumor nontumor discrimination. Irradiated, short living CD38CAR KHYG‐1 cells also showed significant anti‐MM effects in a xenograft model with a humanized bone marrow‐like niche. Finally, CD38CAR KHYG‐1 cells effectively eliminated primary MM cells derived from patients who are refractory to CD38 antibody daratumumab. Taken together, the results of this proof‐of‐principle study demonstrate the potential value of engineering affinity‐optimized CD38CARs in NK cells to establish effective anti‐MM effects, with an excellent safety profile, even in patients who failed to response to most advanced registered myeloma therapies, such as daratumumab.