Preclinical immunotherapy with Cytokine-Induced Killer lymphocytes against epithelial ovarian cancer

Abstract

Despite improvements in surgery and medical treatments, epithelial ovarian cancer (EOC) remains the most lethal gynaecological malignancy. Aim of this study is to investigate the preclinical immunotherapy activity of cytokine-induced killer lymphocytes (CIK) against epithelial ovarian cancers, focusing on platinum-resistant settings. We generated CIK ex vivo starting from human peripheral blood samples (PBMCs) collected from EOC patients. Their antitumor activity was tested in vitro and in vivo against platinum-resistant patient-derived ovarian cancer cells (pdOVCs) and a Patient Derived Xenograft (PDX), respectively. CIK were efficiently generated (48 fold median ex vivo expansion) from EOC patients; pdOVCs lines (n = 9) were successfully generated from metastatic ascites; the expression of CIK target molecules by pdOVC confirmed pre and post treatment in vitro with carboplatin. the results indicate that patient-derived CIK effectively killed autologous pdOVCs in vitro. Such intense activity was maintained against a subset of pdOVC that survived in vitro treatment with carboplatin. Moreover, CIK antitumor activity and tumor homing was confirmed in vivo within an EOC PDX model. our preliminary data suggest that ciK are active in platinum resistant ovarian cancer models and should be therefore further investigated as a new therapeutic option in this extremely challenging setting.Standard therapy of epithelial ovarian cancer (EOC) includes cytoreductive surgery to no residual disease associated with platinum-based chemotherapy 1-3 . Unfortunately recurrence rate of remains high and at the day EOC represent the main cause of death among gynecological neoplasm for women in developed countries 4,5 . It's reported that platinum-based re-challenging brings benefit in platinum-sensitive patients, while platinum-resistant patients are treated with single-agent chemotherapy (e.g., pegylated liposomal doxorubicin 6,7 paclitaxel 8 gemcitabine 9 , topotecan 10,11 , or docetaxel 11,12 ). Several new drugs have been recently approved, such as bevacizumab [13][14][15][16] and PARP inhibitors 17-23 , for BRCA-mutated EOCs, but nevertheless the prognosis remains severe and it is necessary discovered new strategies to prevent tumor spreading, progression and overcome drug resistance.In the last few years strong evidence showed that immunotherapy is effective both in solid and hematological malignancies. Currently, most of the efforts are directed towards immune checkpoint inhibitors (anti PD-1, PD-L1, CTLA4) which are able to induce long lasting remissions in specific settings of metastatic solid tumors (e.g. melanoma, Non small cell lung cancer), although if still in limited numbers of patients [24][25][26][27] . Recently, immune checkpoint inhibitors have shown activity but only in small subsets of EOC patients with BRCA mutations or microsatellite instability (MSI) 28 . Defects in tumor antigen presentation and antigen-presenting machinery are emerging among the possible causes of resistance to immunotherapy with checkpoint inhi...

How can Cytokine-induced killer cells overcome CAR-T cell limits

“…The great peculiarity of such effector cells is the major histocompatibility complex (MHC)-unrestricted lytic capacity towards a wide range of hematological ( 21 , 25 , 29 – 33 ) and solid ( 27 , 34 – 38 ) tumor cells, without the need of prior antigen exposure or priming. CIK cell cytotoxic capacity is exerted by the engagement of natural killer group 2 member D (NKG2D) molecules, which recognize specific ligands known as UL16-binding protein family members (ULBP1–6) and MHC class I-related molecules A and B (MIC A/B) widely expressed on tumor cells ( 39 – 42 ).…”

Clinical Applications of Combined İmmunotherapy Approaches in Gastrointestinal Cancer: A Case-Based Review

“…Favorable outcomes achieved with CIK cell therapy led to increased efforts to improve efficacy with combined approaches. There exists strong preclinical evidence on the synergistic efficacy of proinflammatory cytokines such as interleukins (101)(102)(103)(104) and interferon (105) as well as cytotoxic agents (106), novel small molecule inhibitors (107)(108)(109), immune checkpoint inhibitors (110)(111)(112), monoclonal antibodies (113,114) and dendritic cell (115)(116)(117) or viral-based vaccines (118-120) combined with adoptive cell therapy. Several stromal or intracellular mechanisms implicated in the synergistic activity have been identified.…”

Breast cancer treatment by transplantations of dendritic cells and cytokine-induced killer cells: An update on clinical trials

“…Furthermore, numerous studies proved CIK's ability to treat both hematologic and solid tumors 13,20,21,37,38 . Recently, Capellero et al published a preclinical study; the CIK cells from EOC patients efficiently killed patient-derived ovarian cancer cell lines (pdOVC), with no difference between autologous and allogeneic targets 39 . Also, the study indicated that CIK cells also efficiently killed chemotherapy-survived pdOVC; the killing ability was superior due to the high expression of stress ligand in tumor cells after being treated with carboplatin.…”