Neoadjuvant Immunotherapy for Patients with dMMR/MSI-High Gastrointestinal Cancers: A Changing Paradigm

SIMPLE SUMMARY: Immune checkpoint inhibitors (ICIs) have transformed the treatment of mismatch repair-deficient (MMR-D)/microsatellite instability-high (MSI-H) colorectal cancers. These cancers have a high mutation burden and generate antigens called mutation-associated neoantigens (MANAs). ICIs activate T-cell immunity against these cancers, resulting in significant antitumor activity. Dramatic responses seen in patients with advanced-stage MSI-H gastrointestinal cancers have resulted in rapid clinical development of ICIs for patients with earlier stages of disease. Based on the available evidence, the pathological response observed in this context shows great promise, which encourages the use of ICIs as neoadjuvant therapy. ABSTRACT: Immune checkpoint inhibitors have revolutionized the management of mismatch repair-deficient (MMR-D)/microsatellite instability-high (MSI-H) gastrointestinal cancers, particularly colorectal cancer. Cancers with the MMR-D/MSI-H genotype often carry a higher tumor mutation burden with frameshift alterations, leading to increased mutation-associated neoantigen (MANA) generation. The dramatic response seen with immune checkpoint inhibitors (ICIs), which are orchestrated by MANA-primed effector T cells, resulted in the rapid development of these novel therapeutics within the landscape of MSI-H gastrointestinal cancers. Recently, several clinical trials have utilized ICIs as potential neoadjuvant therapies for MSI-H gastrointestinal cancers and demonstrated deep clinical and pathological responses, creating opportunities for organ preservation. However, there are potential challenges to the neoadjuvant use of ICIs for certain disease types due to the clinical risk of overtreatment for a disease that can be cured through a surgery-only approach. In this review article, we discuss neoadjuvant management approaches with ICI therapy for patients with MSI-H gastrointestinal cancers, including those with oligometastatic disease. We also elaborate on potential challenges and opportunities for the neoadjuvant utilization of ICIs and provide further insight into the changing treatment paradigm of MMR-D/MSI-H gastrointestinal cancers.