How to Best Exploit Immunotherapeutics in Advanced Gastric Cancer: Between Biomarkers and Novel Cell-Based Approaches

Abstract

Despite extensive research efforts, advanced gastric cancer still has a dismal prognosis with conventional treatment options. Immune checkpoint inhibitors have revolutionized the treatment landscape for many solid tumors. Amongst gastric cancer subtypes, tumors with microsatellite instability and Epstein Barr Virus positive tumors provide the strongest rationale for responding to immunotherapy. Various predictive biomarkers such as mismatch repair status, programmed death ligand 1 expression, tumor mutational burden, assessment of tumor infiltrating lymphocytes and circulating biomarkers have been evaluated. However, results have been inconsistent due to different methodologies and thresholds used. Clinical implementation therefore remains a challenge. The role of immune checkpoint inhibitors in gastric cancer is emerging with data from monotherapy in the heavily pre-treated population already available and studies in earlier disease settings with different combinatorial approaches in progress. Immune checkpoint inhibitor combinations with chemotherapy (CT), anti-angiogenics, tyrosine kinase inhibitors, anti-Her2 directed therapy, poly (ADP-ribose) polymerase inhibitors or dual checkpoint inhibitor strategies are being explored. Moreover, novel strategies including vaccines and CAR T cell therapy are also being trialed. Here we provide an update on predictive biomarkers for response to immunotherapy with an overview of their strengths and limitations. We discuss clinical trials that have been reported and trials in progress whilst providing an account of future steps needed to improve outcome in this lethal disease.

NF-κB in Gastric Cancer Development and Therapy

“…Despite intensive investigations towards targeting immune cells, their molecular mediators, and effectors, there is still no established immunotherapeutic strategy for treatment of GC. However, the inhibitors of PD-L1 reached stage 3 clinical trials and demonstrated promising anti-tumor activity in patients with PD-L1-positive GC [ 181 , 182 , 183 ].…”

The Incidence-Based Mortality and Survival Trends in Patients with Gastric Signet Ring Cell Carcinoma

“…Recent advances in targeted therapy, such as trastuzumab deruxtecan (T-DXd), have demonstrated significant survival benefits for HER-2 positive advanced gastric cancer [ 23 ]. More recently, immune checkpoint inhibitors have revolutionized the therapy for patients with advanced gastric cancer [ 24 ]. The phase II KEYNOTE-059 trial first evaluated the safety and efficacy of pembrolizumab in patients with metastatic gastric cancer [ 25 ].…”

Gastric Cancer and the Immune System: The Key to Improving Outcomes?

“…Despite promising options for antibody-based therapies, research on which therapy may be best suited for which patient is still ongoing. Biomarkers that may be used to classify tumors, as well as possibly affect treatment decisions and prognosis, include mismatch repair status, MSI identification, PDL-1 combined positive score (CPS), tumor infiltrating lymphocyte quantification, and tumor mutational burden [ 81 ]. Interestingly, the use of circulating tumor DNA (ctDNA) has the potential to provide data on likelihood of response to ICI and prognosis without requiring a tissue biopsy [ 82 ].…”