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

Area of Science:

• Oncology
• Gastrointestinal Cancer Research
• Immunotherapy

Background:

• Mismatch repair-deficient (MMR-D)/microsatellite instability-high (MSI-H) gastrointestinal cancers, especially colorectal cancer, have been transformed by immune checkpoint inhibitors (ICIs).
• These genotypes often exhibit high tumor mutation burden and frameshift alterations, increasing mutation-associated neoantigen (MANA) generation, which primes effector T cells for response to ICIs.

Purpose of the Study:

• To review neoadjuvant management strategies utilizing ICIs for MMR-D/MSI-H gastrointestinal cancers, including those with oligometastatic disease.
• To discuss the potential challenges and opportunities associated with neoadjuvant ICI therapy in this patient population.
• To provide insights into the evolving treatment paradigm for MMR-D/MSI-H gastrointestinal cancers.

Main Methods:

• Review of recent clinical trials and existing literature on neoadjuvant immune checkpoint inhibitor therapy for MMR-D/MSI-H gastrointestinal cancers.
• Analysis of clinical and pathological response data from neoadjuvant ICI studies.
• Discussion of the implications of these findings for treatment strategies and patient management.

Main Results:

• Neoadjuvant ICIs have demonstrated deep clinical and pathological responses in clinical trials for MSI-H gastrointestinal cancers, suggesting potential for organ preservation.
• The high tumor mutation burden and MANA generation in MMR-D/MSI-H tumors contribute to their sensitivity to ICIs.
• Challenges include the risk of overtreatment in a curable, surgery-only setting for certain disease presentations.

Conclusions:

• Neoadjuvant ICI therapy presents a promising avenue for MSI-H gastrointestinal cancers, offering significant response rates and organ preservation possibilities.
• Careful patient selection and risk-benefit assessment are crucial to mitigate the potential for overtreatment, particularly in early-stage disease.
• The findings highlight a significant shift in the treatment paradigm for MMR-D/MSI-H gastrointestinal cancers, emphasizing the role of immunotherapy in neoadjuvant settings.