Immunotherapy in colorectal cancer: a beacon of hope.

The standard treatment of colorectal cancer (CRC) typically involves a combination of surgery, chemotherapy and radiotherapy. One of the most exciting paradigm shifts in recent times is the use of immunotherapy as part of standard treatment for several tumour types such as melanoma,1 non-small cell lung cancer2 and renal cell carcinoma.3 However, it has not been shown to be very effective in CRC until the past few years when immune checkpoint inhibitors (ICI) produced remarkable results in a subset of patients with CRC characterized by high microsatellite instability (MSI-H) due to deficient DNA mismatch repair (dMMR). In order to understand the mechanisms of action of ICIs, it is important to appreciate the genetic and immunological differences between dMMR and pMMR patients. MMR is a system involved in identifying and repairing mismatched bases during DNA replication and is regulated by 4 key genes, mutL homologue 1 (MLH1), mutS homologue 2 (MSH2), mutS homologue 6 (MSH6), and postmeiotic segregation increased 2 (PMS2). Mutational or epigenetic inactivation of these genes leads to dMMR, which in turn causes accumulation of mutations that often occur at areas of short tandem repetitive DNA sequences called microsatellites, hence also termed MSI-H. Genetic instability due to dMMR/MSI-H is thought to occur in about 15% of CRC,4 and may be sporadic or hereditary in the form of Lynch syndrome. From an immunological standpoint, there are distinct histopathological features associated with a dMMR/MSI-H phenotype, such as a Crohn's-like lymphoid reaction and the presence of tumour-infiltrating lymphocytes. This T-cell-infiltrated tumour microenvironment may be explained by the high tumour mutational burden, leading to generation of high levels of non-self-immunogenic antigens (neoantigens) which stimulates host anti-tumour immune response. However, these tumours can evade immune surveillance by overexpressing programmed death-ligand 1 (PD-L1) which acts on programmed cell death protein 1 (PD-1) receptor on T cells. The latter is a key immune checkpoint that suppresses T cell-mediated immune response under physiological conditions. Therefore, by using ICIs to block the interaction between PD-1 and PD-L1, the anti-tumour activity of T cells can be restored or even enhanced to improve immune response. Initial results of immunotherapy use in non-selective CRC were disappointing, with most studies demonstrating limited efficacy.5, 6 Subsequently, Le et al. hypothesised that dMMR patients were more responsive to anti-PD-1 therapy, due to their higher tumour mutational burden and prominent immune infiltrate, and initiated a phase II trial of pembrolizumab (anti-PD-1) in solid tumours which grouped patients by their MMR status.7 Preliminary results showed that the objective response rate and progression-free survival rate at 20 weeks were 40% and 78% for dMMR metastatic CRC, respectively, compared to 0% and 11% for pMMR metastatic CRC. These encouraging results have prompted further trials to focus on the effect of ICIs broadly across MSI-H solid tumours. In a study that pooled the results of 149 patients with different tumour types, enrolled across 5 single-arm clinical trials (including KEYNOTE-016 and KEYNOTE-164), treatment with pembrolizumab resulted in a 36% objective response rate in metastatic CRC patients and 46% in patients with other tumour types.8 Such was the efficacy of pembrolizumab that the US FDA granted accelerated approval in 2017 for its tissue-agnostic use in patients with dMMR/MSI-H unresectable or metastatic solid tumours, regardless of primary site. Since then, pembrolizumab has been shown to significantly improve progression-free survival, compared to chemotherapy, when received as first-line therapy in patients with dMMR/MSI-H metastatic CRC (KEYNOTE-177).9 Other ICIs have also shown equally promising results, such as nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA-4) in the CheckMate 142 trial.10 Whilst previous studies were mostly in patients with metastatic CRC, more recent studies have shown excellent response to ICIs in patients with earlier stage CRC. In a phase II clinical trial by Cercek et al.,11 patients with dMMR stage II or III rectal adenocarcinoma would receive 3-weekly dostarlimab (anti-PD-1) for 6 months, followed by chemoradiotherapy and surgery, unless a complete clinical response (cCR) was achieved. Remarkably, despite the small sample size and short follow-up, all 12 patients (100%) had cCR after anti-PD-1 therapy and did not undergo further treatment including surgery. Similarly, in the latest NICHE-2 trial where patients with non-metastatic dMMR colon cancer received neoadjuvant nivolumab plus ipilimumab, 95% of patients had major pathological response, with 67% achieving pathological complete response.12 The authors suggested that neoadjuvant immunotherapy could become the standard of care in early colon cancer and potentially allow some patients to consider organ-sparing approaches. It is still unclear why patients with earlier stage CRC have such a significant response compared to those with metastatic CRC but it may be related to variations in the gut microbiome or alternatively, a more intact host immune system unaffected by chemoradiotherapy and where tumour mutational burden is low. At present, the recommendation for use of ICIs is largely limited to patients with metastatic disease, with pembrolizumab being listed on the Pharmaceutical Benefits Scheme in Australia as a first-line treatment option for unresectable or metastatic dMMR CRC since August 2021. Although recent studies have shown excellent efficacy of ICIs in earlier stage dMMR/MSI-H CRC, long-term response durability and survival data is not available so surgery remains the standard of care. However, it begs the question whether ICIs may be considered earlier in the treatment algorithm such as in the neoadjuvant setting. For this reason, universal MMR screening, either through MMR immunohistochemistry or MSI testing (not all MSI originates from dMMR), of all newly diagnosed CRC cases must be performed. This will identify suitable dMMR/MSI-H patients to access immunotherapy via clinical trials to evaluate the use of ICIs in a wider context. Future research should also focus on understanding the mechanisms of immunoresistance in the majority of CRCs (85%) which are associated with chromosomal instability. Developing strategies to convert these immunologically ‘cold’ tumours into ‘hot’ ones, such as combining ICIs with conventional therapies, is the focus of many ongoing studies. One such example is the Ave-Rec trial which is evaluating the addition of avelumab (anti-PD-L1) following long-course chemoradiotherapy in patients with resectable, locally advanced rectal cancer.13 Through broadening the susceptibility of other subsets of CRC to immunotherapy, its full potential may be unleashed, shining a beacon of hope for the treatment of CRC. Open access publishing facilitated by The University of Melbourne, as part of the Wiley - The University of Melbourne agreement via the Council of Australian University Librarians.