Regulatory T (T
) cells, an immunosuppressive subset of CD4
T cells characterized by the expression of the master transcription factor forkhead box protein P3 (FOXP3), are a component of the immune ...system with essential roles in maintaining self-tolerance. In addition, T
cells can suppress anticancer immunity, thereby hindering protective immunosurveillance of neoplasia and hampering effective antitumour immune responses in tumour-bearing hosts, thus promoting tumour development and progression. Identification of the factors that are specifically expressed in T
cells and/or that influence T
cell homeostasis and function is important to understanding cancer pathogenesis and to identifying therapeutic targets. Immune-checkpoint inhibitors (ICIs) have provided a paradigm shift in the treatment of cancer. Most immune-checkpoint molecules are expressed in T
cells, but the effects of ICIs on T
cells, and thus the contributions of these cells to treatment responses, remain unclear. Notably, evidence indicates that ICIs targeting programmed cell death 1 (PD-1) might enhance the immunosuppressive function of T
cells, whereas cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors might deplete these cells. Thus, although manipulation of T
cells is a promising anticancer therapeutic strategy, approaches to controlling these cells require further research. Herein, we discuss novel insights into the roles of T
cells in cancer, which can hopefully be used to develop T
cell-targeted therapies and facilitate immune precision medicine.
Advances in cancer biology and sequencing technology have enabled the selection of targeted and more effective treatments for individual patients with various types of solid tumour. However, only ...three molecular biomarkers have thus far been demonstrated to predict a response to targeted therapies in patients with gastric and/or gastro-oesophageal junction (G/GEJ) cancers: HER2 positivity for trastuzumab and trastuzumab deruxtecan, and microsatellite instability (MSI) status and PD-L1 expression for pembrolizumab. Despite this lack of clinically relevant biomarkers, distinct molecular subtypes of G/GEJ cancers have been identified and have informed the development of novel agents, including receptor tyrosine kinase inhibitors and monoclonal antibodies, several of which are currently being tested in ongoing trials. Many of these trials include biomarker stratification, and some include analysis of circulating tumour DNA (ctDNA), which both enables the noninvasive assessment of biomarker expression and provides an indication of the contributions of intratumoural heterogeneity to response and resistance. The results of these studies might help to optimize the selection of patients to receive targeted therapies, thus facilitating precision medicine approaches for patients with G/GEJ cancers. In this Review, we describe the current evidence supporting the use of targeted therapies in patients with G/GEJ cancers and provide guidance on future research directions.
Differences in clinical outcomes between advanced gastric cancer (AGC) in Asia and that in other regions have been discussed for a long time, although no major significant differences in molecular ...profiles have been reported. The anti-human epidermal growth factor receptor 2 antibody trastuzumab and the anti-vascular endothelial growth factor receptor 2 monoclonal antibody ramucirumab were both approved as a treatment for AGC on the basis of global phase 3 trials including Japan. In recent years, others new agents for treatment of AGC have been investigated in global or Asian studies. Randomized phase 2 trials in Japan showed a higher response rate to S-1 plus leucovorin and oxaliplatin than to standard S-1 plus cisplatin, which is the rationale for an ongoing phase 3 trial in Asia (SOLAR trial). A recent global phase 1 trial of the anti-programmed cell death 1 monoclonal antibody pembrolizumab showed similar efficacy results in Asian patients and non-Asian patients, which led to large global phase 2 and phase 3 studies. Although the perspective of treatment of AGC in the near future depends on the results of ongoing large clinical trials, individualized choice of treatment based on more detailed molecular information will become important.
Immune checkpoint inhibitors (ICIs) such as anti-programmed cell death-1 (PD-1) or programmed cell death ligand-1 (PD-L1) monoclonal antibodies have prolonged survival in various types of ...malignancies, including advanced gastric cancer (AGC). Nivolumab, a monoclonal anti-PD-1 antibody, showed an improvement in overall survival at a later-line therapy in unselected AGC patients in the ATTRACTION-2 study or in combination with chemotherapy as first-line therapy in the global CheckMate-649 study. Another monoclonal anti-PD-1 antibody, pembrolizumab, showed single agent activity in tumors with high microsatellite instability or high tumor mutational burden. Furthermore, a recent KEYNOTE-811 study demonstrated significant improvement in response rate with pembrolizumab combined with trastuzumab and chemotherapy for HER2-positive AGC. Based on these results, ICIs are now incorporated into standard treatment for AGC patients. As a result of pivotal clinical trials, three anti-PD-1 antibodies were approved for AGC: nivolumab combined with chemotherapy as first-line treatment or nivolumab monotherapy as third- or later-line treatment in Asian countries; pembrolizumab for previously treated microsatellite instability-high (MSI-H) or tumor mutational burden-high AGC, or pembrolizumab combined with trastuzumab and chemotherapy for HER2-positive AGC in the United States; and dostarlimab for previously treated MSI-H AGC in the United States. However, a substantial number of patients have showed resistance to ICIs, highlighting the importance of the better selection of patients or further combined immunotherapy. This review focused on molecular and immunological profiles, pivotal clinical trials of ICIs with related biomarkers, and investigational immunotherapy for AGC.
Background
Hyperprogressive disease (HPD) during treatment with anti-programmed death-1/programmed death-ligand 1 monoclonal antibodies has anecdotally been reported in some types of cancers, but is ...not well-characterized in patients with advanced gastric cancer (AGC).
Methods
Total 62 AGC patients treated with nivolumab in a single institution from September 2017 to April 2018 were enrolled in this study. Tumor responses were assessed according to Response Evaluation Criteria in Solid Tumors version 1.1, and HPD was defined as ≥ two fold increase in tumor growth rate. Clinicopathological and molecular characteristics associated with HPD were also investigated.
Results
Thirteen of 62 patients (21%) developed HPD after nivolumab treatment. Overall survival (OS) and progression-free survival (PFS) were significantly shorter in patients with HPD than in patients without HPD (median OS: 2.3 months vs. not reached,
P
< 0.001; median PFS: 0.7 months vs. 2.4 months,
P
< 0.001). Liver metastases (77% vs. 41%), Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1 or 2 (77% vs. 29%), and a large sum of target lesion diameters at baseline (median 104.2 mm vs. 44.9 mm) were significantly associated with HPD. Absolute neutrophil count (ANC) and C-reactive protein (CRP) level significantly increased in the first 4 weeks in only patients with HPD.
Conclusions
HPD was observed in AGC patients treated with nivolumab and correlated with some clinicopathological characteristics. Elevations in ANC and CRP levels upon treatment might indicate HPD.
Human epidermal growth factor receptor 2 (HER2, also known as ERBB2) amplification or overexpression occurs in approximately 20% of advanced gastric or gastro-oesophageal junction adenocarcinomas
. ...More than a decade ago, combination therapy with the anti-HER2 antibody trastuzumab and chemotherapy became the standard first-line treatment for patients with these types of tumours
. Although adding the anti-programmed death 1 (PD-1) antibody pembrolizumab to chemotherapy does not significantly improve efficacy in advanced HER2-negative gastric cancer
, there are preclinical
and clinical
rationales for adding pembrolizumab in HER2-positive disease. Here we describe results of the protocol-specified first interim analysis of the randomized, double-blind, placebo-controlled phase III KEYNOTE-811 study of pembrolizumab plus trastuzumab and chemotherapy for unresectable or metastatic, HER2-positive gastric or gastro-oesophageal junction adenocarcinoma
( https://clinicaltrials.gov , NCT03615326). We show that adding pembrolizumab to trastuzumab and chemotherapy markedly reduces tumour size, induces complete responses in some participants, and significantly improves objective response rate.
Recently, immune checkpoint inhibitors such as anti-programmed cell death-1 (PD-1) or programmed cell death ligand-1 (PD-L1) monoclonal antibodies have improved the overall survival of various types ...of cancers including advanced gastric cancer (AGC). Until now, two ant-PD-1 inhibitors were approved for AGC in Japan: nivolumab as third- or later-line treatment for AGC and pembrolizumab for previously treated patients with microsatellite instability-high tumours. However, a limited number of patients achieved clinical benefit, highlighting the importance of the better selection of patients or additional treatment to overcome resistance to PD-1/PD-L1 blockade. This review focused on pivotal clinical trials, biomarkers and novel combination therapy of immune checkpoint inhibitors forAGC.
Trastuzumab deruxtecan (T-DXd) is a novel anti-human epidermal growth factor receptor 2 (HER2) antibody–drug conjugate composed of a monoclonal anti-HER2 antibody and a topoisomerase I inhibitor, ...DX-8951 derivative (an exatecan derivative). T-DXd showed potential anti-tumor activities in HER2-positive gastric cancer cell lines and xenograft models. In the randomized, phase II trial DESTINY-Gastric01, T-DXd demonstrated a significantly higher objective response rate as a primary endpoint and a longer overall survival as a secondary endpoint in patients with pretreated HER2-positive advanced gastric cancer (AGC). Although adverse events caused by T-DXd were generally manageable, approximately 10% of patients experienced treatment-related interstitial lung disease. Based on the results of the DESTINY-Gastric01 trial, T-DXd was approved for HER2-positive pretreated AGC in Japan. This study reviews the preclinical and clinical data of T-DXd for treating HER2-positive gastric cancer.
Immune checkpoint blockade has provided a paradigm shift in cancer therapy, but the success of this approach is very variable; therefore, biomarkers predictive of clinical efficacy are urgently ...required. Here, we show that the frequency of PD-1
CD8
T cells relative to that of PD-1
regulatory T (T
) cells in the tumor microenvironment can predict the clinical efficacy of programmed cell death protein 1 (PD-1) blockade therapies and is superior to other predictors, including PD ligand 1 (PD-L1) expression or tumor mutational burden. PD-1 expression by CD8
T cells and T
cells negatively impacts effector and immunosuppressive functions, respectively. PD-1 blockade induces both recovery of dysfunctional PD-1
CD8
T cells and enhanced PD-1
T
cell-mediated immunosuppression. A profound reactivation of effector PD-1
CD8
T cells rather than PD-1
T
cells by PD-1 blockade is necessary for tumor regression. These findings provide a promising predictive biomarker for PD-1 blockade therapies.
Claudins (CLDNs) are a family of major membrane proteins that form components of tight junctions. In normal tissues, CLDNs seal the intercellular space in the epithelial sheets to regulate tissue ...permeability, paracellular transport, and signal transduction. Claudin18.2 (CLDN18.2), a member of the CLDN family, is expressed specifically in gastric mucosal cells in normal tissue, and its expression is often retained in gastric cancer cells. CLDN18.2 is ectopically expressed in many cancers other than gastric cancer such as esophageal cancer, pancreatic cancer, biliary tract cancer, non-small-cell lung cancer, and ovarian cancer. Structurally, CLDN18.2 is localized on the apical side of the cell membrane and has extracellular loops capable of binding monoclonal antibodies. Upon malignant transformation, CLDN18.2 is exposed to the cell surface of the whole membrane, which enables the binding of monoclonal antibodies. Based on these characteristics, CLDN18.2 was considered to be optimal for target therapy, and zolbetuximab was developed which is a first-in-class chimeric immunoglobulin G1 monoclonal antibody highly specific for CLDN18.2. It binds to CLDN18.2 on the tumor cell surface and stimulates cellular and soluble immune effectors that activate antibody-dependent cytotoxicity and complement-dependent cytotoxicity. Recently, zolbetuximab combined with chemotherapy demonstrated a survival benefit in patients with CLDN18.2-positive and HER-2-negative gastric or gastroesophageal junction cancers in the global phase III SPOTLIGHT and GLOW trials. From these clinically meaningful results, CLDN18.2-targeting therapy including zolbetuximab has attracted a lot of attention. In this review, we summarize the clinical implications of CLDN18.2-positive gastric or GEJ cancer, and CLDN18.2-targeting therapy, mainly for zolbetuximab.
PDF
