Our aim is to provide a panoramic view of the different immune-based strategies used for gastric cancer management and discuss the data of the most significant clinical trials. In detail, firstly we describe the therapeutic approaches that utilize the monoclonal antibodies while in the second part we analyze the cell-based anti-gastric cancer treatments.
Immunotherapy for gastric cancer: monoclonal antibodies
1, Anti-epidermal growth factor receptor (cetuximab/panitumumab/matuzumab)
The EGFR hyperexpression shows a relationship with augmented invasion and more unfavorable prognosis of patients with esophago-gastric cancers. Cetuximab obstructs the lignad junction with the EGFR, promotes EGFR internalization and also, can start the immune-mediated cytotoxicity. Besides, a phase I study reported a stable disease (SD), for 7 mo, in one refractory esophago-gastric cancers patient, treated with panitumumab. Combination of matuzumab with the ECX regimen (epirubicin/cisplatin/capecitabine) registered encouraging results as first-line therapy in patients with EGFR+ gastric cancer. The ORR in 20 evaluable patients was 65% with a median TTP of 5.2 mo.
2, Anti-HER2/ERBB2 (trastuzumab)
HER-2/neu (ERBB2) is part of the ERBB TK receptor family. The ligand of these receptors leads to homo/ hetero-dimerization of the receptors and with their formation displaying a distinct hierarchy. In this system, HER-2/neu has a key role because each receptor with a specific ligand promotes the association with Her-2/neu. This predilection is more influenced by Her-2/neu hyperexpression, as seen in numerous types of human tumor cells. The anti-HER2/neu moAb treatment that has been tested in esophago-gastric cancers patients is Trastuzumab, that exercises its role by different ways: blocking HER-2 receptor dimerization, favoring the receptor demolition and promoting the cytotoxicity.
3, Anti-vascular endothelial growth factor (bevacizumab)
The action of most powerful angiogenic factor, VEGF, is started by linking to various high-affinity trans-membrane receptors, most remarkably VEGFR types 1 and 2. VEGF is over-expressed in different cancers and besides, in esophageal and gastric cancer the hyperexpression correlates with cancer stage, bad prognosis and reduced survivaL. Also, the moAb bevacizumab is an anti-VEGF monoclonal antibody, that associated with the chemotherapy increases the ORR and TTP in patients with colon, NSCLC and breast cancer. It seems that bevacizumab have a double anti-cancer effect: as anti-angiogenic factor and also increasing chemotherapy drug delivery, favoring the decrease of interstitial fluid pressures.
4, Anti-hepatocyte growth factor/mesenchymal-epithelial transition factor (rilotumumab)
The cell surface receptor c-MET [mesenchymal-epithelial transition factor (MET)] and its ligand hepatocyte growth factor (HGF) are potential therapeutic targets in esophagogastric cancer. Physiological MET tyrosine kinase activation is mediated by binding of HGF, leading to signal transduction down multiple downstream pathways, including those involving Ras, PI3K, mTOR, STAT3, and NF-κB. Additionally, the HGF/MET axis can stimulate tumor endothelial cells, thereby altering the tumor microenvironment and promoting angiogenesis. Physiological MET signaling can be altered by ligand/receptor overexpression or gene amplification as well as MET gene mutations. Specifically, MET gene amplification is a driver in some esophagogastric cancers. Rilotumumab is a human moAb to HGF. In a randomized phase II study, patients with newly diagnosed gastric cancer were randomized to receive 1 of 2 doses of rilotumumab (15 mg/kg or 7.5 mg/kg) in combination with ECX (epirubicin, cisplatin, capecitabine) chemotherapy or chemotherapy alone.
Immunotherapy for gastric cancer: Cell based immunotherapy
1, Therapies with T cell
Essentially exist two different therapeutic protocols of T cell-based anti-cancer treatment: (1) cytotoxic T lymphocytes (CTL); (2) tumor infiltrating lymphocytes (TIL).
Elevated efficiency was obtained upon inducing survivin-derived peptide-specific CTL from mononuclear cells isolated from blood of healthy donors. The induced CTLs showed specific lysis against tumor cells in vitro, and vs primary cell cultures isolated from GC patients. The CTLs killed HLA-A-10201/12402 colon and gastric cancer MCAK+ cells, as well as the peptide-pulsed target cells, in an HLA-l restricted manner. These results prospect the opportunity of designing peptide-based immunotherapeutic treatments for patients with MCAK+ gastric cancer. preclinical/clinical evidence supports the idea that CIK cell immunotherapy can be a successful anti-gastric cancer treatment.
TILs have been used for immunotherapy of gastric cancer. TILs are potentially especially useful because they already recognize some tumor-specific antigens in that tumor. Adoptive immunotherapy with TILs has provided promising results in preclinical studies in sarcoma. A clinical study of adoptive immunotherapy with tumor-associated lymphocytes in combination with chemotherapy in gastric cancer resulted in a longer 50% survival with the combination of adoptive immunotherapy and chemotherapy than with
chemotherapy alone. Cytokine induced killer cells are rapidly proliferating lymphocytes with strong anti-tumor activity. Clinical studies have confirmed a survival benefit in gastric cancer patients treated with chemotherapy combined with cytokine induced killer
cells compared to chemotherapy alone.
Dendritic cell-based vaccination
Dendritic cells pulsed with HER-2/neu-derived peptides can induce specific T-cell responses in patients with gastric cancer;
Dendritic cell vaccination with MAGE peptide is a novel therapeutic approach for gastrointestinal carcinomas;
A phase I study of active immunotherapy with carcinoembryonic antigen RNA-pulsed, autologous human cultured dendritic cells in patients with metastatic malignancies expressing carcinoembryonic antigen;
A pilot study of active immunotherapy with HER2/neu intracellular domain protein-pulsed, autologous, cultured dendritic cells in patients with no evidence of disease after standard treatment for HER2/neu expressing malignancies;
A phase I study of active Immunotherapy with autologous dendritic cells infected with CEA-6D expressing fowlpox -tricom in patients with advanced or metastatic malignancies expressing CEA;
A Phase I clinical trial of mTOR inhibition with rapamycin for enhancing intranodal dendritic cell vaccine induced anti-tumor immunity in patients with NY-ESO-1 expressing solid tumors.
Treatments by using NK cells
About gastric cancer, a recent study evaluated the NK number in 72 patients with gastric adenocarcinoma and its correlation with patient survival. The conclusions are that patients with high concentration of NK cells showed a higher survival rate when compared to the low concentration, especially in the advanced stage.
In the future, combination may be needed to for gastric cancer immunotherapy to take advantages of all the method, which may benefit more for gastric cancer immunotherapy.
Niccolai E et al. Gastric cancer and the epoch of immunotherapy approaches. World Journal of Gastroenterology : WJG. 2015;21(19):5778-5793.