Neoadjuvant immunotherapy in colorectal cancer beyond immune checkpoint inhibitors: emerging from bench to bedside

Colorectal cancer (CRC) is the second most frequent cancer in both men and women, and of concern increasing in the younger population. Despite the progress in treatment, still up to half of CRC patients will develop metastasis. Immunotherapy consists of an arsenal of different managements that in many aspects has revolutionized cancer therapy. Monoclonal antibodies, chimeric antigen receptor (CAR) T-cell receptor gene modified T-cells and immunization and/or vaccination are different immunotherapies used in cancer treatment. Large trials in metastatic CRC, such as CheckMate 142 and KEYNOTE-177, have proven the efficacy of immune checkpoint inhibitors (ICI). The ICI drugs, targeting the cytotoxic T-lymphocyte associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) are now part of first-line treatment of dMMR/MSI-H metastatic CRC. However, ICIs are gaining a novel role in management of primary operable CRC after preliminary results from early-phase clinical studies in both colon and rectal cancer. Neoadjuvant ICI in operable colon and rectal cancer is hence becoming a clinical reality, while not quite yet adopted as a routine use. However, with some answers comes more questions and challenges. In this review article we aim to give an overview over different modes of immunotherapy to treat cancer with an emphasis on ICIs and their relevance to CRC, describe some of the progresses made in immunotherapy overall, with potential mechanisms, some of the concerns and, some highlight for the way forward.