One-Step Method for Instant Generation of Advanced Allogeneic NK Cells.

Daniel Y Lee,Young-Wook Won,Kwang Suk Lim,Gabriel M Valencia,Minjin Jung,David A Bull

doi:10.1002/advs.201800447

Abstract

Conventional combinatorial anticancer therapy has shown promising outcomes; still, a significant interest in developing new methods to reinforce and possibly merge chemotherapy and immunotherapy persists. Here, a new one‐step method that immediately modifies immune cells into a targeted form of chemoimmunotherapy through spontaneous and rapid incorporation of hydrophobized antibody–drug conjugates (ADCs) on the surface of immune cells is presented. Therapeutic objectives of this approach include targeted delivery of a potent chemotherapeutic agent to avoid adverse effects, enhancing the mobilization of infused immune cells toward tumor sites, and preserving the intense cytotoxic activities of immune cells against tumor cells. The embedding of hydrophobized ADCs on the immune cell membrane using the strategy in this study provides noninvasive, nontoxic, and homogenous modifications that transiently arm immune cells with highly potent cytotoxic drugs targeted toward cancer cells. The resulting surface‐engineered immune cells with ADCs significantly suppress the tumor growth and drive the eradication of target cancer cells through combinatorial anticancer effects. This novel strategy allows convenient and timely preparation of advanced chemoimmunotherapy on a single immune cell to treat various types of cancer.

Highlights

Conventional combinatorial anticancer therapy has shown promising outbeneficial synergy for maximizing the clinical antitumor activity.[1,2] Effective comes; still, a significant interest in developing new methods to reinforce chemoimmunotherapy requires that and possibly merge chemotherapy and immunotherapy persists
The embedding of hydrophobized antibody–drug conjugates (ADCs) on the immune cell membrane using the strategy in this study provides noninvasive, nontoxic, and homogenous chemotherapy and immunotherapy that meet the above criteria would represent a new platform for the development of targeted cancer chemoimmunotherapy
These results demonstrate that T-DM1 is embedded on the natural killer (NK) cell surface without internalization and the surface engineering of NK cells with ADCs does not interfere with the NK cell receptor accessibility, suggesting that the inherent cytolytic activity of NK cells is retained upon the surface engineering (Figure 2e)

Summary

Results and Discussion

T-DM1 was generated through the expression of trastuzumab (TZ) in mammalian cells followed by DM1 conjugations.[14,15] Prepared T-DM1 was subsequently hydrophobized by attaching DMPE-PEG-NHS, resulting in the production of DMPE-PEGT-DM1 (Figure S1, Supporting Information). In SK-BR-3 cells and Calu-3 cells, we found that the level of cancer cell death induced by SE-NK/T-DM1 cells was greater than that induced by NK cell or T-DM1+NK cotreatment, while no significant cell death was noticed in MDA-MB-231 cells (Figure 4d–f) This is due to the fact that a higher number of SE-NK/T-DM1 cells remained bound to SK-BR-3 cells and Calu-3 cells, resulting in an augmented level of anticancer activity. To determine whether or not NK cells were activated upon incorporation of DMPE-PEG-T-DM1 on their surface, we assessed the level of CD107a expression, a prominent degranulation marker,[23,24] on SE-NK/T-DM1 cells and unmodified NK cells upon engaging the target cancer cells Other creative antibody engineering methods, such as using single chain variable fragment (scFv) and altering Fc region to reduce Fc receptor binding affinity, can be employed as an alternative strategy for our surface engineering purpose.[44,45,46]

Conclusion

Experimental Section

Conflict of Interest