Neoadjuvant immunotherapy in primary and metastatic colorectal cancer

Abstract

Background: Colorectal cancer (CRC) is the second most common solid organ cancer. Traditional treatment is with surgery and chemotherapy. Immunotherapy has recently emerged as a neoadjuvant therapy that could change treatment strategy in both primary resectable and metastatic CRC.

Methods: A literature review of PubMed with a focus on studies exploring upfront immunotherapy in operable CRC, either for primary resectable stage I-III cancers or for (potentially) operable liver metastasis.

Results: Immune checkpoint blockade by the programmed cell death 1 (PD-1) receptor inhibitors nivolumab and pembrolizumab and the cytotoxic T cell-associated protein 4 (CTLA-4) inhibitor ipilimumab has shown good results in both early-stage and advanced CRC. The effects of immune checkpoint inhibitors have so far been demonstrated in small phase I/II studies and predominantly in treatment-refractory stage IV disease with defect Mismatch repair (dMMR). However, recent data from phase I/II (NICHE-1) studies suggest an upfront role for immunotherapy in operable stage I-III disease. By blocking crucial immune checkpoints, cytotoxic T cells are activated and release cytotoxic signals that initiate cancer cell destruction. The very high complete response rate in dMMR operable CRC with neoadjuvant immunotherapy with nivolumab and ipilimumab, and even partial pathological response in some patients with proficient MMR (pMMR) CRC, calls for further attention to patient selection for neoadjuvant treatment, beyond MMR status alone.

Conclusion: Early data on the effect of immunotherapy in CRC provide new strategic thinking of treatment options in CRC for both early-stage and advanced disease, with prospects for new trials.

Fig. 1

Immunotherapy by immune checkpoint blockage in colorectal cancer Simplistic overview of mechanisms of T cell activation/inactivation in the tumour microenvironment. The inactive state of T cells in immune ‘cold’ tumours (on the left). Major histocompatibility complex (MHC)-T cell receptor (TCR)-dependent signalling demonstrates immune evasion by tumour cells expressing the inhibitory ligand PD-L1, which binds to PD-1 on T cells (and B7 molecules) which bind to CTLA-4. Cancer cell engagement with inhibitory ligands (against PD-1 and CTLA-4) prevents cytotoxic killing of tumour cells. PD-L1 binding initiates a signalling cascade that stimulates conversion of effector T cells to regulatory T cells (Tregs). Tumours in the active state (immune ‘hot’ tumours on right side of panel). CD8⁺ T cells recognize tumour-associated antigens expressed on MHC class I on tumour cells via the TCR, which results in cytotoxic killing of tumour cells via release of granzymes and perforins. Inhibitory ligands against PD-1 and CTLA-4 are blocked by immune checkpoint inhibitors, allowing active T cell function towards cancer cells. Several associated mechanisms are involved, in addition, including dendritic cells that serve as a biologic immune intermediate for neoantigen delivery, with an ability to augment the immune response through cytokine release. CTLA-4, cytotoxic T lymphocyte-associated protein 4; PD-1, programmed cell death 1; PD-L1, PD-1 ligand.

Fig. 2

Context- and stage-based prevalence of consensus molecular subtypes in early-stage and advanced colorectal cancer Depicted are the main features of each of the four subtypes (a) and the context-dependent distribution across disease stages (b). The actual CMS distribution may vary between trials and studies, based on inclusion criteria, with direct impact on study population outcomes. Data are approximated from several different studies.

Fig. 3

Variation in the immune landscape from early- to advanced-stage CRC The model of immune ‘hot’ and ‘cold’ tumours across the spectrum of primary and stage IV disease is illustrated, based on. Several other factors are involved, including age and sex of patient, tumour sidedness (with more dMMR in right-sided colon cancers being immune hot). Patterns of clinical scenarios associated with the immune profile are emerging such as association of multiple small disseminated liver metastases found in immune ‘cold’ tumours. The clinical presentation of CRC, together with mismatch repair status, immune cell quantification, and molecular features such as tumour mutational burden, may help delineate appropriate and personalized use of immunotherapy and the design of new trials.