Current Strategy to Treat Immunogenic Gastrointestinal Cancers: Perspectives for a New Era

Abstract

Since pembrolizumab, an anti-programmed death-1 (PD-1) antibody, showed a dramatic response to immunogenic cancers with microsatellite instability-high (MSI-H) and/or deficient mismatch repair (dMMR) in the pilot clinical trial KEYNOTE-016, subsequent studies have confirmed durable responses of anti-PD-1 inhibitors for MSI-H/dMMR solid tumors. As immunotherapy is described as a “game changer,” the therapeutic landscape for MSI-H/dMMR solid tumors including gastrointestinal cancers has changed considerably in the last decade. An MSI/MMR status has been established as the predictive biomarker for immune checkpoint blockades, playing an indispensable role in the clinical practice of patients with MSI-H/dMMR tumors. Immunotherapy is also now investigated for locally advanced MSI-H/dMMR gastrointestinal cancers. Despite this great success, a few populations with MSI-H/dMMR gastrointestinal cancers do not respond to immunotherapy, possibly due to the existence of intrinsic or acquired resistance mechanisms. Clarifying the underlying mechanisms of resistance remains a future task, whereas attempts to overcome resistance and improve the efficacy of immunotherapy are currently ongoing. Herein, we review recent clinical trials with special attention to MSI-H/dMMR gastrointestinal cancers together with basic/translational findings, which provide their rationale, and discuss perspectives for the further therapeutic development of treatment in this field.

Mucinous Cystadenocarcinoma of the Breast with Bone Metastases: First Case Report and Literature Review

“…Numerous investigations posit the efficacy of checkpoint inhibitors (CPIs) in addressing MSI-H tumors. CPIs have been approved for the treatment of MSI-H gastrointestinal cancers [33]. However, the occurrence of mismatch repair protein (MMR) deficiency in breast cancer is notably uncommon, comprising merely 1–2% of cases overall and approximately 6% in the context of triple-negative breast cancer [34].…”

Survival impact of microsatellite instability in stage II gastric cancer patients who received S-1 adjuvant monotherapy after curative resection

“…It remains to be determined whether the S-1 adjuvant treatment impacted positively or negatively on such immune suppression tumors apparent in recurrent MSI-H cases in the present study. Developments in perioperative treatment with ICIs for early MSI-H tumors are under way 20 . Although the efficacy of such ICI-based therapy is generally high for these tumors, it is possible that the clinical benefit is limited to those cases with a poor immune environment, given that MSI-H tumors inherently have a good prognosis 20 .…”

“…Developments in perioperative treatment with ICIs for early MSI-H tumors are under way 20 . Although the efficacy of such ICI-based therapy is generally high for these tumors, it is possible that the clinical benefit is limited to those cases with a poor immune environment, given that MSI-H tumors inherently have a good prognosis 20 . On the other hand, the expression of CTA genes was associated with recurrence in MSS tumors, consistent with previous results showing that the expression of MAGE and GAGE genes is associated with poor prognosis in GC 21 – 23 .…”

Immunotherapy as a promising treatment strategy for dmmr colorectal cancer with brain metastasis: a case report

“…The response rates of MSI-H solid tumors to immune checkpoint inhibitors (ICIs) are approximately 40% in the pan-cancer setting, with some responses showing long-term durability [21] . Tumor mutational burden (TMB) has also been explored as a predictive biomarker for immunotherapy response, and high TMB in MSI-H/dMMR tumors has been associated with increased and durable responses to ICIs [22] . In gastrointestinal cancers, including those with MSI-H/dMMR, a TMB-high status may further refine the efficacy of immunotherapy [23] .…”