Engineered affinity-optimized CD38 chimeric antigen receptor (CAR) T-cells demonstrated potential for multiple myeloma (MM) treatment in a preclinical study published in HemaSphere.
CAR-T cell therapy is a growing treatment for hematologic cancers, but it faces challenges with lack of universal donors, long manufacturing times, and graft-vs-host disease with allogeneic T cells. More convenient strategies are needed to increase access to CAR-based therapies.
The CD38 molecule is highly and uniformly expressed on MM cells. This preclinical study evaluated the use of affinity-optimized CD38CARs in KHYG-1 cells, an immortal natural killer (NK) cell line, for MM. Previous research has evaluated generating CAR carriers from NK cells, which are thought to lead to less cytokine release syndrome and other toxicities associated with CAR-T cell therapy.
It’s unclear whether NK cells are suitable as CAR carriers for CD38 antigen, so the authors sought to evaluate the potential efficacy and safety of CD38CAR NK cells. The authors evaluated the cells for in vivo and ex vivo anti-MM efficacy. The study used MM cell lines and primary MM cells derived from patients as target cells. The study examined toxicity in nonmalignant hematopoietic cells.
Patients refractory to daratumumab often have CD38 down regulation within the first 3 to 6 months, which encouraged the study authors to test the CD38CARs in this patient population. They used cells from 6 patients with daratumumab refractory MM. The CD38CAR KHYG-1 cells could eliminate the MM cells.
The authors suggested that the affinity CD38CARs may not be as effective in cells with low levels of CD38, although this study was not able to determine a cutoff of CD38 expression.
In vivo experiments, however, found that the cells had an anti-tumor effect for a short period, which would require multiple administrations. The in vivo experiments also had little curative anti-tumor effect.
Overall, the CD38CAR KHYG-1 cells showed anti-MM effects, even in MM cells from patients refractory to the CD38 antibody daratumumab. The study also had low or no cytotoxicity in the nonmalignant cells.
The study results suggested that “off the shelf” products may be possible with engineered affinity-optimized CD38CARs in KHYG-1 cells as potential treatment for MM.
Disclosure: This research was supported by ONK Therapeutics. Please see the original reference for a full list of disclosures.
Stikvoort A, van der Schans J, Sarkar S, et al. CD38-specific chimeric antigen receptor expressing natural killer KHYG-1 cells: a proof of concept for an “off the shelf” therapy for multiple myeloma. Hemasphere. 2021;5(7):e596. doi:10.1097/HS9.0000000000000596