Integrating Immune Checkpoint Inhibitors With Total Neoadjuvant Therapy in Proficient Mismatch Repair Rectal Cancer.

Area of Science:

• Oncology
• Immunotherapy
• Rectal Cancer Treatment

Background:

• Locally advanced rectal cancer (LARC) management has advanced with total neoadjuvant therapy (TNT).
• Immune checkpoint inhibitors (ICIs) are effective in MSI-H colorectal cancer but limited in pMMR/MSS tumors due to poor immunogenicity.
• Chemoradiotherapy (CRT) or short-course radiotherapy (SCRT) can enhance tumor immunogenicity, making pMMR/MSS tumors more responsive to immunotherapy.

Purpose of the Study:

• To review the clinical evidence and mechanistic rationale for integrating ICIs into TNT for pMMR/MSS LARC.
• To highlight the importance of optimal sequencing and chemotherapy intensity in TNT-ICI regimens.
• To explore the potential for improved pathological complete response (pCR) and clinical complete response (cCR) rates with organ preservation.

Main Methods:

• Review of recent clinical studies (UNION, TORCH, PRECAM) investigating ICIs combined with TNT for LARC.
• Analysis of the immunomodulatory effects of CRT/SCRT on pMMR/MSS tumors.
• Consolidation of mechanistic data supporting the synergy between TNT and ICIs.

Main Results:

• TNT-ICI regimens have demonstrated higher pCR and cCR rates (40%-60%) compared to traditional CRT-ICI combinations.
• Optimal sequencing and chemotherapy intensity within TNT are crucial for maximizing therapeutic synergy and minimizing lymphodepletion.
• CRT/SCRT acts as an immunomodulator, converting "cold" pMMR/MSS tumors into "hot" immune-responsive environments.

Conclusions:

• Integrating ICIs into TNT represents a promising strategy for improving treatment outcomes in pMMR/MSS LARC.
• TNT-ICI offers a pathway to higher pCR and cCR rates, facilitating organ-preserving treatment approaches.
• Further research into optimal TNT-ICI sequencing and chemotherapy regimens is warranted to maximize efficacy and minimize toxicity.