Novel Immunological Approaches in the Treatment of Locally Advanced Rectal Cancer

Chemoradiotherapy (CRT) followed by radical surgery is one of the standard therapies for patients with locally advanced rectal cancer (LARC). Various combination therapies have been developed to improve the efficacy of preoperative therapies. One promising approach is the combination of ionizing radiation and immune checkpoint inhibitors (ICIs) because it enhances both local and distal immunogenic efficacy according to several xenograft models. To date, promising short-term efficacy results of 23% to 37.5% of the pathological complete response (pCR) rate have been reported in clinical trials investigating the combination of CRT and ICIs in patients with microsatellite stable (MSS) LARC. In patients with high-level microsatellite instability (MSI-H) LARC, CRT followed by ICI also achieved a 60% (3/5) pCR rate according to the data of the VOLTAGE study, suggesting increased efficacy of ICIs in this subgroup, albeit with a small sample size. In patients with MSS LARC, programmed cell death-ligand 1 tumor proportion score positivity, elevated CD8/effector regulatory T cell ratio, higher immune-score, consensus molecular subtype 1, and higher tumor mutational burden appear to be positive predictors of ICIs efficacy. In addition, various prospective studies combining CRT with ICI, chemotherapy, and target agents are currently being conducted. To confirm the survival benefits of these approaches, confirmatory phase III trials are needed.