15353-j-veluchamy

5 Towards UCB-NK cells treatment in colorectal cancer | 121 Introduction Colorectal cancer (CRC) is the fourth leading cause of cancer related deaths in the world 1 . Despite substantial advances in the treatment of metastatic CRC (mCRC) over the last decades that have contributed to better survival rates 2,3 , the disease is still frequently fatal. Monoclonal antibodies targeting the Epidermal Growth Factor Receptor (EGFR) pathway, such as panitumumab and cetuximab are approved for the treatment of patients with advanced CRC either in combination with chemotherapy or, as monotherapy, in chemo- refractory conditions 4 . Cetuximab (CET) and panitumumab block the interaction between EGFR and its ligands, thus inhibiting the downstream RAS-signalling cascade and tyrosine kinase activation 5 . However, mutations in tumour suppressor genes and proto-oncogenes in EGFR signalling pathways, such as in RAS, BRAF and PIK3CA are common in patients with CRC. These mutations represent a poor prognostic marker and render anti-EGFR mAbs ineffective, leaving 42% of the chemo-refractory mCRC population without standard treatment option 6, 7 . Besides the blockade of the EGFR-ligand interaction on tumor cells, therapeutic mAbs can also interact with Natural Killer (NK) cells triggering antibody-dependent cell-mediated cytotoxicity (ADCC) 8-10 , and this can translate into superior anti-tumor effects 11 . Two NK cell subsets can be identified based on the expression of CD16, the low affinity FcγRIIIa receptor. The majority of NK cells are CD56 dim CD16 + , and play an active role in NK cell cytotoxicity and are capable of performing ADCC upon IgG 1 engagement via CD16, whereas CD56 bright CD16 - NK cells are mainly immune regulatory in function, secreting cytokines, and are less cytotoxic than CD56 dim cells 12 . NK cell functions are tightly regulated by a delicate balance between activating receptors (like the natural cytotoxicity receptors NKp46, NKp30 and NKp44, or C-type lectin-like receptor NKG2D) 13 and Major Histocompatibility Complex (MHC) class I binding inhibitory receptors, including Killer-cell immunoglobulin- like receptors (KIRs), LIR1/ILT2 and NKG2A/CD94 14 . The importance of NK cells in controlling tumors has been extensively demonstrated since their identification 40 years ago 15-17 . Several studies have shown a dysfunctional phenotype and poor infiltration of NK cells in the CRC tissue from early stages on, together with an immunosuppressive tumor microenvironment 18,19 . Hence, various strategies e.g. using cytokines or therapeutic ADCC enhancing mAbs, have been explored to increase NK cell numbers and function and to enhance their trafficking to tumor sites 20 . Another approach entails the adoptive transfer of in vitro manipulated and expanded autologous or allogeneic NK cells. Autologous NK cells so far have failed to demonstrate significant therapeutic benefits in solid tumors 21-23 . Therefore, the focus has shifted to the development of allogeneic NK cells as a potential adoptive cell therapy for treatment in solid tumors. Previously, we demonstrated that the combination of allogeneic activated PBNK (A-PBNK) cells and CET can effectively target RAS mutant (RAS mut ) CRC tumors 24 .