Immune Checkpoint Inhibitors in pMMR Metastatic Colorectal Cancer: A Tough Challenge

Federica Marmorino, Alessandra Boccaccino, Marco Maria Germani, Alfredo Falcone, Chiara Cremolini, Federica Marmorino, Alessandra Boccaccino, Marco Maria Germani, Alfredo Falcone, Chiara Cremolini

Abstract

The introduction of checkpoint inhibitors provided remarkable achievements in several solid tumors but only 5% of metastatic colorectal cancer (mCRC) patients, i.e., those with bearing microsatellite instable (MSI-high)/deficient DNA mismatch repair (dMMR) tumors, benefit from this approach. The favorable effect of immunotherapy in these patients has been postulated to be due to an increase in neoantigens due to their higher somatic mutational load, also associated with an abundant infiltration of immune cells in tumor microenvironment (TME). While in patients with dMMR tumors checkpoint inhibitors allow achieving durable response with dramatic survival improvement, current results in patients with microsatellite stable (MSS or MSI-low)/proficient DNA mismatch repair (pMMR) tumors are disappointing. These tumors show low mutational load and absence of "immune-competent" TME, and are intrinsically resistant to immune checkpoint inhibitors. Modifying the interplay among cancer cells, TME and host immune system is the aim of multiple lines of research in order to enhance the immunogenicity of pMMR mCRC, and exploit immunotherapy also in this field. Here, we focus on the rationale behind ongoing clinical trials aiming at extending the efficacy of immunotherapy beyond the MSI-high/dMMR subgroup with particular regard to academic no-profit studies.

Keywords: immune checkpoint inhibitors; metastatic colorectal cancer; microsatellite stable; proficient DNA mismatch repair.

Conflict of interest statement

Federica Marmorino, Alessandra Boccaccino and Marco Maria Germani declare no conflict of interest. Alfredo Falcone has received honoraria from Amgen, Lilly, Merck, Roche, and SERVIER; research funding from Amgen (Inst), Bayer (Inst), Merck (Inst), MSD (Inst), Roche (Inst), Sanofi (Inst), and SERVIER (Inst); funding for travel accommodations, expenses from Amgen, Bayer, Merck, Roche, and SERVIER; served as consultant and advisory role for Amgen, Bayer, Bristol-Myers Squibb, Lilly, Merck, Roche, and SERVIER. Chiara Cremolini received honoraria from Amgen, Bayer, Roche, and SERVIER; research funding from Merck; funding for travel accommodations, expenses from Roche and SERVIER; served as consultant or advisory role for Amgen, Bayer, and Roche; as member of the Speakers’ Bureau for SERVIER.

Figures

Figure 1
Figure 1
Approaches to enhance immunogenicity of proficient mismatch repair (pMMR) colorectal cancer. CTL: cytotoxic Lymphocytes; BRAFi: BRAF inhibitors; EGFRi: EGFR inhibitors; MEKi: MEK inhibitors; TME: Tumor Microenvironment.

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