CD38-specific chimeric antigen receptor expressing natural killer KHYG-1 cells: A proof of concept for an "Off the Shelf" therapy for multiple myeloma

Arwen Stikvoort, Jort van der Schans, Subhashis Sarkar, Renée Poels, Ruud Ruiter, Jyoti Naik, Huipin Yuan, Joost D. de Bruijn, Niels W. C. J. van de Donk, Sonja Zweegman, Maria Themeli, Richard Groen, Michael O'Dwyer*, Tuna Mutis*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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 CD38high MM cell lines as well as primary MM cells ex vivo. Importantly, the intermediate affinity CD38CAR transduced KHYG-1 cells spared CD38neg or CD38int 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.
Original languageEnglish
Article numbere596
JournalHemaSphere
Early online date2021
DOIs
Publication statusPublished - Jul 2021

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