An Antibody Designed to Improve Adoptive NK-Cell Therapy Inhibits Pancreatic Cancer Progression in a Murine Model

Abstract

Natural killer (NK) cells are primary immune cells that target cancer cells and can be used as a therapeutic agent against pancreatic cancer. Despite the usefulness of NK cells, NK-cell therapy is limited by tumor cell inhibition of NK-cell homing to tumor sites, thereby preventing a sustained antitumor immune response. One approach to successful cancer immunotherapy is to increase trafficking of NK cells to tumor tissues. Here, we developed an antibody-based NK-cell-homing protein, named NK-cell-recruiting protein-conjugated antibody (NRP-body). The effect of NRP-body on infiltration of NK cells into primary and metastatic pancreatic cancer was evaluated in vitro and in murine pancreatic ductal adenocarcinoma models. The NRP-body increased NK-cell infiltration of tumors along a CXCL16 gradient (CXCL16 is cleaved from the NRP-body by furin expressed on the surface of pancreatic cancer cells). CXCL16 induced NK-cell infiltration by activating RhoA via the ERK signaling cascade. Administration of the NRP-body to pancreatic cancer model mice increased tumor tissue infiltration of transferred NK cells and reduced the tumor burden compared with that in controls. Overall survival of NRP-body-treated mice (even the metastasis models) was higher than that of mice receiving NK cells alone. In conclusion, increasing NK-cell infiltration into tumor tissues improved response to this cancer immunotherapy. The combination of an NRP-body with NK-cell therapy might be useful for treating pancreatic cancer.

Targeting natural killer cells in solid tumors

“…46,88 An antibody-based NK cell-homing protein, the NK cell-recruiting protein-conjugated antibody (NRP-body), has recently been developed. 89 The NRPbody increased NK cell infiltration along a CXCL16 gradient in a murine primary and metastatic pancreatic ductal adenocarcinoma tumor model. NRP-body administration increased the infiltration of transferred NK cells into tumor tissues and reduced tumor burden relative to that in controls, thereby increasing the overall survival.…”

State of the Art of Natural Killer Cell Imaging: A Systematic Review

“…Ex vivo studies revealed a strong reduction of tumor volume in these mice if compared with the control group. Imaging was used with the same purpose by Lee et al [65] that evaluated the efficacy of an NK-cell-recruiting protein-conjugated antibody (NRP-body) in primary and metastatic pancreatic duct adenocarcinoma in murine animal models. They labeled ex vivo expanded NK cells from healthy donors with 1,1′-Dioctadecyl-3,3,3′,3′-Tetramethylindotricarbocyanine iodide (DiR) and demonstrated increased NK infiltration into tumors with a significant anti-cancer effect.…”

The Immune Microenvironment in Pancreatic Cancer

“…The therapeutic effect was mediated by T cells and NK cells. Moreover, administration of the NK cell-recruiting protein (NRP)-conjugated antibody (NRP-body) increased NK cell infiltration into tumor tissue and reduced the tumor burden [ 106 ]. Additionally, two clinical trials have illustrated that the combination of allogeneic NK cell immunotherapy with percutaneous irreversible electroporation enhances the progression-free survival and overall survival in stage III PDAC and extends the overall survival in stage IV PDAC [ 107 , 108 ].…”