Application of immune checkpoint inhibitors and microsatellite instability in gastric cancer

Abstract

In this editorial we comment on the article by Li published in the recent issue of the World Journal of Gastroenterology. We focus specifically on the application of immune checkpoint inhibitors (ICIs) and microsatellite instability (MSI) in gastric cancer (GC). The four pillars of GC management have long been considered, including surgery, chemotherapy, radiotherapy and targeted therapy. However, immunotherapy has recently emerged as a ”fifth pillar”, and its use is rapidly expanding. There are four principal strategies for tumor immunotherapy: ICIs, tumor vaccines, adoptive immunotherapy and nonspecific immunomodulators. Of them, ICIs are the most advanced and widespread type of cancer immunotherapy for GC. Recent breakthrough results for ICIs have paved the way to a new era of cancer immunotherapy. In particular, inhibition of the PD-1/PD-L1 axis with ICIs, including nivolumab and pembrolizumab, has emerged as a novel treatment strategy for advanced GC. Unfortunately, these therapies are sometimes associated with often subtle, potentially fatal immune-related adverse events (irAEs), including dermatitis, diarrhea, colitis, endocrinopathy, hepatotoxicity, neuropathy and pneumonitis. We must be aware of these irAEs and improve the detection of these processes to prevent inappropriate discharges, emergency department revisits, and downstream complications. Recent studies have revealed that MSI-high or mismatch- repair-deficient tumors, regardless of their primary site, have a promising response to ICIs. So, it is important to detect MSI before applying ICIs for treatment of GC.

Key Words: Gastric cancer; Immune checkpoint inhibitors; Microsatellite instability; Immunotherapy; Immune-related adverse events

Core Tip: The immune checkpoint proteins including PD-1/PD-L1, cytotoxic T-lymphocyte antigen-4 play significant roles in the field of cancer immunotherapy. As a result, monoclonal antibodies block these immune checkpoint proteins have been utilized broadly in patients with gastric cancer (GC). However, the treatment-emergent adverse events of autoimmune-like toxicities in patients treated with immune-related immune checkpoint inhibitors (ICIs) have also been observed. These may be related to microsatellite instability (MSI). So, it is important to detect MSI before applying ICIs for treatment of GC.

INTRODUCTION

Though the incidence and mortality of gastric cancer (GC) have been decreasing in past 10 years, it is still the third major cause of cancer-related death worldwide[1]. Many factors were well-known as key to the pathogenesis of GC, such as dietary habits, family history, smoking and Helicobacter pylori or Epstein–Barr virus infection[2]. The prognosis of GC is affected by many factors, such as cancer stage, location, histological type, biological behavior, and therapeutic measures. As a standard therapy, curative resection with or without perioperative chemotherapy worked well in many patients. For unresectable or metastatic advanced GC, chemotherapy using platinum compounds, 5-fluorouracil, docetaxel, paclitaxel and irinotecan is a standard therapy[3]. Furthermore, trastuzumab is seen as a first-line treatment for HER2-positive advanced GC patients and ramucirumab can be used as second-line treatment for advanced GC[4]. Results from CTLA-4 and PD-1 monoclonal antibodies have started a new era of cancer immunotherapy[5]. In particular, inhibition of the PD-1/PD-L1 axis with immune checkpoint inhibitors (ICIs), including nivolumab and pembrolizumab, has emerged as a novel treatment strategy for advanced GC[6]. PD-1 and CTLA-4 are coinhibitory receptors expressed on the surface of T cells to negatively regulate T-cell-mediated immune responses. However, tumor cells exploit these inhibitory molecules to induce tumor tolerance and T-cell exhaustion. Accordingly, ICIs such as anti-CTLA-4, anti-PD-1, and anti-PD-L1 can attach to these coinhibitory receptors, thereby reactivating the immune response against tumor cells[7]. However, different anti-PD-1, anti-PD-L1 and anti-CTLA-4 ICIs show different efficacy in different GC patients. This is a complex clinical and research issue. Therapeutic efficacy may be related to microsatellite stability. ICIs have reshaped cancer therapy, and indications for their use are likely to continue growing. While ICIs have demonstrated clinical benefit in several cancers, including GC, they are also associated with a broad range of immune-related adverse events (irAEs), which can affect almost every organ. When we use ICIs to treat GC, we need to choose appropriate drugs or combine them with other treatments based on different patients and tumor-treatment-related molecules. At the same time, we need to pay attention to the adverse effects of ICIs, especially autoimmune diseases such as pneumonia, hepatitis and encephalitis, and identify and intervene as soon as possible.

TREATMENT OF GC WITH ICIS

There are many types of ICIs approved by the US Food and Drug Administration (FDA): PD-1 inhibitive antibodies (e.g., pembrolizumab, nivolumab, cemiplimab, sintiliumab, Camrelizumab); anti-CTLA-4 antibodies (e.g., ipilimumab, tremelimumab); and anti-PD-L1 antibodies (e.g., atezolizumab, avelumab and durvalumab, envafolimab). Clinical trials of nivolumab and pembrolizumab showed that they significantly prolonged overall survival (OS) in patients with advanced GC. Clinical trials of ipilimumab and durvalumab are ongoing. Negative result was reported in the trial as third-line therapy for advanced GC patients treated with avelumab comparing with chemotherapy[8].

PEMBROLIZUMAB

Pembrolizumab is a monoclonal antibody that blocks the PD-1/PD-L1 pathway. It was approved in US for treatment of multiple types of tumors[9]. For cases of unresectable locally advanced, recurrent or metastatic GC, pembrolizumab is a better choice for HER2-positive patients considering its high objective response rate (ORR)[10]. In phase 3 trials (NCT02370498 and NCT02494583), pembrolizumab demonstrated consistent results in GC patients; compared to chemotherapy, a trend toward improved OS and ORR, as well as reducing treatment-related adverse events was observed[11,12]. For HER2-positive GC patients, combination of pembrolizumab, trastuzumab, and chemotherapy would be preferred. A clinical trial (NCT03409848) claimed the additional benefit that combination therapy can bring to patients comparing with previous treatment protocols in HER2-positive GC patients[13]. In another trial, namely KEYNOTE-059/Cohort 1, pembrolizumab-treated advanced GG patients achieved an ORR of 11.6%[14]. On a contrary, studies with pembrolizumab monotherapy as secondary-line treatment failed to meet the primary efficacy endpoint comparing with paclitaxel for advanced GC (KEYNOTE-061 and NCT02370498)[15].

NIVOLUMAB

Nivolumab is the first mAb that suppresses PD-1 by blocking the interaction between PD-L1, PD-L2 and PD-1 receptor[16]. Nivolumab and pembrolizumab shared similar mode of action. In vitro studies showed that nivolumab completely abolished the suppressive effects of T regulatory cells on naive CD4⁺ T-cell proliferation and partially restored interferon-γ production[17]. Irrespective of HER2 status, Nivolumab is recommended as part of systemic treatment regimens. Nivolumab is the first PD-1 inhibitor to show positive efficacy and safety profile, combining with chemotherapy vs chemotherapy alone in previously untreated patients with advanced GC, gastro-esophageal junction cancer, or esophageal adenocarcinoma. Nivolumab in combination with chemotherapy established a new standard first-line treatment for these patients[18].

MICROSATELLITE INSTABILITY AND IMMUNE CHECKPOINT INHIBITORS

In the National Comprehensive Cancer Network guidelines, microsatellite instability (MSI) is related to prognosis in several types of cancers and is often used for decision of chemotherapy regimen in stage II colon cancer. Cancers with MSI were found with extensive presence of immune checkpoint ligands and robust immunogenicity, high sensitivity to immunotherapy, and may lead to higher possibility of resistance to chemotherapies. However, the association between MSI and the prognosis of GC remains unclear. Zhu et al[19] showed that MSI-high (MSI-H) GC has better prognosis, along with reduced risks of lymph node metastasis, tumor invasion and mortality. In GC, the incidence of MSI-H ranges from 8.2% to 37%. It might be caused by the limited number of cases been investigated. Both nivolumab monotherapy and combination therapy with ipilimumab have a positive benefit/risk ratio in chemotherapy-resistant gastroesophageal adenocarcinoma. Pembrolizumab was also approved as a therapeutic alternative for MSI-H tumors[20,21]. FDA endorsed pembrolizumab to be used for patients with refractory advanced GC who expressed PD-L1, or with unresectable/metastatic MSI-high/mismatch repair deficiency (dMMR) solid tumors such as GC. PD-1 expression and MSI-high/dMMR can be used as predictive biomarkers of ICI-based therapy in GC[22]. Therefore, it is recommended to performing detection of PD-1/PD-L1 and dMMR is recommended to guide immunotherapy in GC patients, especially those with advanced cancer.

TOXICITY OF ICIS

ICIs represent a potent class of drugs for a growing number of neoplastic disorders. After the original approval for patients suffered from advanced melanoma, oncologists extended their use to the treatment of a few other advanced cancers, including non-small cell lung cancer, GC and renal cell carcinoma. However, the treatment-emergent adverse events of autoimmune-like toxicities in patients treated with immune-related ICIs have also been observed. Known as irAEs, which are experienced by up to two thirds of patients[23]. Because the overactive immune response is not limited to the tumor-specific lymphocytes, these irAEs could potentially affect any organs and systems, including gastrointestinal, dermatological, hepatic, pancreatic, endocrine, ocular and neurological toxicity, and pneumonitis. The most common irAEs are gastrointestinal toxicity, hepatitis and pneumonitis.

Gastrointestinal toxicity

Diarrhea and colitis usually occur 6–7 wk after therapy initiation and are more common with anti-CTLA-4 antibodies[24]. Anti-CTLA-4 therapy associates more (7%) with severe colitis, compared with anti-PD-1 therapy (1.8%)[25]. When these irAEs occur, corticosteroids should be tapered over a period of 4–6 wk to prevent early relapses. In patients who are unable to tape off their corticosteroid treatments or have no response to intravenous corticosteroids in 2–3 d, infliximab can be considered in these patients with severe irAEs[26].

Pulmonary toxicity

Pneumonitis is a severe irAE affects to approximately 5% patients receiving ICIs, especially those who were treated with anti-PD-1 comparing with anti-CTLA-4 therapy, with a median time to presentation of almost 3 mo[27]. The diagnosis of drug-induced pneumonitis should be based on the appropriate assessment of infectious etiologies or malignant pulmonary infiltration. ICI therapy might be paused for mild pneumonitis patients[28]. For moderate cases, clinicians need to withhold ICI therapy until symptomatic resolution. Patients can be treated with 1–2 mg/kg/d prednisone or 0.5–1 mg/kg/d methylprednisolone tapered over a period of 4–6 wk to prevent early relapses. For severe patients, ICI therapy should be permanently discontinued and patients should be hospitalized and treated with high corticosteroid doses (e.g., intravenous methylprednisolone, 1–2 mg/kg/d), additional ventilator-assisted mechanical ventilation will be considered if needed[29].

Liver toxicity

All grades of hepatitis happen more frequently with anti-CLTA-4 (10%) than with anti-PD-1 or anti-PD-L1 therapy (5%), and it often occurs within 8–12 wks after initiatial therapy[24]. Ipilimumab combines with an anti-PD-1/PDL-1 agent would cause hepatitis with 30% incidence rate, much higher than ipilimumab or anti-PD-1/PD-L1 monotherapy[30]. Corticosteroid can only be used for ICI-induced hepatitis when alanine aminotransferase or aspartate aminotransferase values exceeds three times the upper limit of normal[31].

CONCLUSION

GC ranks the third leading cause of cancer-related mortality worldwide[32]. As a standard therapy, curative resection with or without perioperative chemotherapy worked well in many patients. For unresectable or metastatic advanced GC, chemotherapy using drugs such as platinum compounds, fluoropyrimidines, docetaxel, paclitaxel and irinotecan is a standard therapy[33]. Targeted therapy and ICIs have also been proven efficient for advanced GC[34]. Li et al[35] systematically analyzed studies related to immunotherapy for GC. They also explored research hotspots in the advances of GC immunotherapy development, as well as the strength and weakness of different immunotherapy modalities. ICIs started a new era of cancer immunotherapy. Immunotherapy with ICIs has dramatically improved the treatments in multiple types of tumors and changed the outcomes in a great number of patients with advanced or metastatic cancers including GC. Although immunotherapy is effective in the late stages of GC, ICIs can induce various irAEs, limiting their use in many patients. The gastrointestinal irAEs including diarrhea, colitis or hepatitis are frequently observed. Therefore, early diagnosis and action against these irAEs are crucial to maximize durability of treatment while managing toxicity. Comprehensive genomic research could help to define reliable biomarkers and tailor an individualized treatment strategy. Existing biomarkers like PD-L1 and MSI can be predictive of treatment response. The creation of anti-PD-1 mAb for the treatment of MSI-H/dMMR tumors significantly changed the treatment strategies of cancer. MSI status can be seen as an acceptable marker for immunotherapeutic response. Li et al[35] predicted future developmental trends in immunotherapy for GC based on the direction and stage of those ongoing trials. His work can help improve our understanding of the latest advances and future development direction in GC immunotherapy. However, the current treatment of tumors, including GC, is a complex issue. Despite the continued emergence of new treatment methods in recent years and the improvement of treatment effects, there are still many problems that require attention and resolution.