Natural Killer Cell-Based Cancer Immunotherapies: From Immune Evasion to Promising Targeted Cellular Therapies

Abstract

Immunotherapies based on natural killer (NK) cells are among the most promising therapies under development for the treatment of so far incurable forms of leukemia and other types of cancer. The importance of NK cells for the control of viral infections and cancer is supported among others by the findings that viruses and tumors use a multitude of mechanisms to subvert and evade the NK cell system. Infections and malignant diseases can further lead to the shaping of NK cell populations with altered reactivity. Counter measures of potential therapeutic impact include the blocking of inhibitory interactions between NK cell receptors and their cellular ligands, the enhancement of activating receptor signals, and the infusion of large numbers of ex vivo generated and selected NK cells. Moreover, the specific cross-linking of NK cells to their target cells using chimeric antigen receptors or therapeutic bi-/trispecific antibody reagents is a promising approach. In this context, NK cells stand out by their positive effects and safety demonstrated in most clinical trials so far. Based in part on results of the recent EC-sponsored project "NATURIMMUN" and considering additional published work in the field, we discuss below new developments and future directions that have the potential to further advance and establish NK cell-based therapies at the clinics on a broader scale.

Keywords: bispecific antibodies; cell therapy; checkpoint inhibitors; chimeric antigen receptors; immune evasion; immunotherapy; natural killer cells.

Figure 1

NK cell-based immunotherapies. Standard therapy for high-risk leukemia includes high-dose chemotherapy, followed by hematopoietic stem cell transplantation. Patients, who do not reach remission or suffer from early relapse thereafter, have a poor prognosis and are in urgent medical need for advanced therapies. Current immunotherapeutic developments and phase I/II trials include checkpoint inhibitors for inhibitory NK receptors, infusion of expanded and activated autologous or allogeneic NK cells, and targeting of NK cells to cancer cells. The latter can be done by modification of NK cells with CAR or by application of multispecific reagents to cross-link NK cells with cancer cells. These immunotherapies should reduce relapse rates and constitute promising additional treatment options for high-risk patients. PB, peripheral blood; CBSC, cord blood stem cell; CAR, chimeric antigen receptor; NK, natural killer.