Neoadjuvant immunotherapy and colorectal cancer treatment: Implications for the primary role of surgery

For their parallel strands of pioneering work beginning in the 1990 s which led to the discovery of anticancer immune checkpoint inhibitor therapy, or immunotherapy (IT), Allison and Honjo were jointly awarded the Nobel Prize in Physiology or Medicine in 2018 [1]. First successfully applied to patients with melanoma, IT represents a generational breakthrough in the management of multiple cancers and research in this field is growing exponentially. Immunotherapy has been applied to colorectal cancer (CRC) relatively recently and, to date, success has focussed on the mismatch repair deficient (dMMR) subset [2]. Failure of intrinsic DNA repair machinery in dMMR CRCs generates a high tumour mutational burden and resultant immunogenic neoantigens attract a brisk immune response. Enhancement of this response through inhibition of programmed death1 (PD1) and other checkpoint proteins represents the rationale for successful IT in this CRC subset. IT, in particular with pembrolizumab, has been demonstrated to be effective, with durable response, against dMMR metastatic CRC and is now considered the standard of care for patients with this subset of disease [3– 6]. However, dMMR CRC accounts for only 5% of patients with metastatic disease [6]. As such, there is an urgent need to leverage benefit from IT for the 95% of CRC patients with pMMR stage IV disease [7]. Avenues being explored include manipulation of the gut microbiome to optimise response to IT, and use of vaccines to stimulate the immune system and turn “cold” tumours “hot” prior to IT [8]. AntiPD1 therapy has recently been applied in the neoadjuvant setting to locally advanced, nonmetastatic dMMR rectal cancer, with exciting, albeit preliminary, results [9]. Furthermore, given successes in treatment with IT of early stage melanoma, lung and bladder cancer, the exploratory NICHE1 study has applied neoadjuvant double agent (ipilimumab and nivolumab) IT to patients with dMMR and MMR proficient (pMMR) early colon cancer with remarkable results [10]. Treatments were well tolerated. One hundred percent of n = 20 dMMR tumours and 27% of n = 15 pMMR tumours showed some pathological response, notably with 60% complete pathological response in the dMMR group. The NICHE studies may pave the way towards treating with neoadjuvant IT all patients with dMMR early stage CRC and potentially also some patients with pMMR early stage CRC. Early stage disease may be more responsive to IT due to lower host immune suppression and higher Tcell infiltrates [11]. Although dMMR tumours appear most responsive, as in other studies, of interest is the subset of pMMR tumours which showed some response to IT, predicted by quantification of CD8+ and PD1+ Tcell subsets [10]. This begs the question might some assessment of immune response better identify a subset of pMMR CRCs responsive to IT? Not all dMMR CRCs have heavy inflammatory infiltrates and not all pMMR CRCs are devoid of inflammation, for example the highly immunogenic, ultramutated, polymerase epsilon (POLE)mutant subset [12]. Assessment of CD3+ and CD8+ Tcell subsets by Immunoscore® has been reported to be a stronger predictor of patient survival than MMR status [13]. However, Immunoscore® has not as yet been demonstrated to predict response to IT. Developments in digital pathology [14], multiplex imaging and analysis tools utilising artificial intelligence [15] enable more sophisticated approaches to quantification of tumour immune cell infiltrates, including assessments of spatial heterogeneity [16]. Such approaches have yielded better prognostic stratification of patients with dMMR CRC by immune subgroups based on tumour infiltrating lymphocytes [16]. Specifically, within the CD3low subset of tumours, a high level of heterogeneity was associated with worse survival but may represent the subset most amenable to IT. Such sophisticated spatial assessment of immune response may be considered in the design of future IT trials. However, an added complexity is that, if considering neoadjuvant IT, the assay in question must be applicable to diagnostic endoscopic biopsy specimens, rather than surgical resections, and it must be assumed that the luminally procured specimen provides an accurate representation of the tumour as a whole. As inflammatory response is typically assessed at the invasive tumour front as well as at the tumour core, and endoscopic biopsies will likely sample neither of these regions, this may prove a further obstacle to implementation of an immune assessment based on endoscopic biopsy material. In contrast, MMR status is readily and accurately discerned from biopsy material, making it a more attractive biomarker in this regard. In conclusion, the development of IT represents a landmark in treatment options for many different cancer types, including CRC. The outworkings of current IT clinical trials, some exploring combination approaches with chemotherapy and/or radiotherapy, are awaited with interest with regard to optimal patient selection and optimal treatment pathways for dMMR and pMMR subsets of CRC