Resistance to immune checkpoint inhibitors in advanced gastro-oesophageal cancers

Abstract

Immune checkpoint inhibitors (ICIs) have altered the treatment paradigm across a range of tumour types, including gastro-oesophageal cancers. For patients with any cancer type who respond, ICIs can confer long-term disease control and significantly improve survival and quality of life, but for patients with gastro-oesophageal cancer, ICIs can be transformative, as durable responses in advanced disease have hitherto been rare, especially in those patients who are resistant to first-line cytotoxic therapies. Results from trials in patients with advanced-stage gastro-oesophageal cancer have raised hopes that ICIs will be successful as adjuvant and neoadjuvant treatments in early-stage disease, when the majority of patients relapse after potential curative treatments, and several trials are ongoing. Unfortunately, however, ICI-responding patients appear to constitute a minority subgroup within gastro-oesophageal cancer, and resistance to ICI therapy (whether primary or acquired) is common. Understanding the biological mechanisms of ICI resistance is a current major research challenge and involves investigation of both tumour and patient-specific factors. In this review, we discuss the mechanisms underlying ICI resistance and their potential specific applications of this knowledge towards precision medicine strategies in the management of gastro-oesophageal cancers in clinical practice.

Current Progress and Future Perspectives of Immune Checkpoint in Cancer and Infectious Diseases

“…The intrinsic mechanisms are composed of lack of tumor antigen presentation, alteration of several inhibitory signaling pathways, and upregulation of other immune checkpoints. The extrinsic mechanisms are predominantly referred to as various elements in the TME (Baxter et al, 2021). To reverse the resistance and ameliorate patients' symptoms, researchers came up with the idea to turn the "cold" immune response to "hot."…”

“…The intrinsic mechanisms are composed of lack of tumor antigen presentation, alteration of several inhibitory signaling pathways, and upregulation of other immune checkpoints. The extrinsic mechanisms are predominantly referred to as various elements in the TME ( Baxter et al, 2021 ). To reverse the resistance and ameliorate patients’ symptoms, researchers came up with the idea to turn the “cold” immune response to “hot.” The strategies applied under such fundamental idea consist of turning down the volume of inhibitory immune signals, triggering T-cell priming, increasing the costimulatory signals, and modulation of the TME ( Attili et al, 2021 ; Weiss and Sznol, 2021 ).…”

Phase II study of ceralasertib (AZD6738) in combination with durvalumab in patients with advanced gastric cancer

“…Open access who respond to ICIs often develop acquired resistance. 6 However, limited treatment options exist once resistance develops, highlighting the need for further novel therapies or strategies that can increase the proportion of patients, including salvage patients with ICI resistance that can benefit from ICIs. The recent approval of ICIs for tumors with defective mismatch repair has made it possible to investigate the role of DNA damage repair (DDR) defects in sensitizing cancer to ICI therapy.…”

“…Furthermore, patients who respond to ICIs often develop acquired resistance. 6 However, limited treatment options exist once resistance develops, highlighting the need for further novel therapies or strategies that can increase the proportion of patients, including salvage patients with ICI resistance that can benefit from ICIs.…”

Tumor vessel normalization and immunotherapy in gastric cancer

“… 157 The ATTRACTION-4 study investigated nivolumab in combination with chemotherapy in an Asian population, including patients with GC; PFS was improved, but no difference in OS between the two groups was observed (mOS: 17.5 versus 17.2 months; HR = 0.9, p = 0.259). 158 In the phase III ATTRACTION-4 study, which was conducted in Asian countries without patients selected based on PD-L1 expression, increased nivolumab chemotherapy resulted in improved PFS, despite a higher proportion of patients receiving follow-up therapy (66%) than in CheckMate-649. 159 …”