Evaluation of allogeneic and autologous membrane-bound IL-21–expanded NK cells for chronic lymphocytic leukemia therapy

Abstract

Successes with anti-CD20 antibodies in chronic lymphocytic leukemia (CLL) and enhanced activity of Fc-engineered versus unmodified antibody therapy suggest a potentially impactful role for natural killer (NK) cells and other innate immune cells in controlling this disease. Stimulated natural killer cells have shown promise as a cellular therapy but their application has been constrained by limited expansion capacity and low cytotoxic activity against CLL cells. Here, we demonstrate that both healthy donor-derived and CLL patient-derived NK cells expand rapidly when stimulated with feeder cells expressing membrane-bound IL-21 and have potent cytotoxic activity against allogeneic or autologous CLL cells. Combination with anti-CD20 antibodies significantly enhances NK recognition and killing of CLL targets. As any CLL immune therapy would likely be given in combination, we assess commonly-used treatments and demonstrate that ibrutinib has mixed suppressive and protective effects on expanded NK cells whereas expanded NKs are highly resistant to venetoclax. We demonstrate efficacy in vivo in two xenograft mouse models of human CLL that support building upon a regimen of venetoclax and obinutuzumab with mbIL-21-expanded NK cells. Collectively, these data support development of mbIL-21-expanded NKs combined with the CD20 antibody obinutuzumab and venetoclax in the treatment of CLL.

Therapeutic potential of interleukin-21 in cancer

“…CLL patient-derived NK cells expanded in the same conditions exhibit increased cytotoxicity against autologous or allogeneic CLL cells. In OSU-CLL and Mec1 cell line xenograft mouse models treatment with expanded NK cells from healthy donors and obinutuzumab and IL-2 significantly increased survival ( 96 ).…”

Cellular Therapy in Chronic Lymphocytic Leukemia: Have We Advanced in the Last Decade?

“…To overcome the challenges in ex vivo NK cell processing, modified protocols propose activation by Epstein-Barr virus lymphoblastoid cells and expansion of the NK cell population in the presence of IL-2 and IL-15 [100][101][102][103]. Furthermore, when using nongenetically modified NK cells, the combinational approach is suggested to be considered, given that both autologous and allogeneic NK cells stimulated with feeder cells expressing membranebound IL-21 showed high cytotoxic activity when combined with anti-CD20 antibodies [104,105].…”

Natural Killer Cells in Chronic Lymphocytic Leukemia: Functional Impairment and Therapeutic Potential

“…Similarly, another group demonstrated the in vitro anti-CLL cytotoxicity of a CAR-NK expressing CD19 CAR, high-affinity non-cleavable CD16, and a membrane-bound IL-15/IL-15R fusion molecule [ 265 ]. Most recently, our lab tested the expansion of NK cells using membrane-bound IL-21 (mbIL-21) expressing feeder cells, demonstrating that this stimulation produces high numbers of NK cells with potent anti-CLL activity in vitro and in vivo, including both allogeneic and autologous targets [ 266 ]. The administration of a targeted antibody here is required.…”