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

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.

Precision Approaches in the Management of Colorectal Cancer: Current Evidence and Latest Advancements towards Individualizing the Treatment

“…Collectively, these data support testing for dMMR in patients with CRC and demonstrate the variable efficacy of systemic treatment, including standard chemotherapy targeted anti-PD1 agents, in selected dMMR patients. Recent and ongoing trials investigating the use of immune checkpoint inhibitors in the treatment of CRC are summarized in Table 2 and Table 3 [ 53 , 54 , 55 , 56 , 59 , 60 , 61 , 62 ].…”

“…Despite these findings, several challenges remain in the realm of clinical applications for immune checkpoint inhibitors in mCRC treatment, particularly in microsatellite stable disease (MSS). It is postulated that MSS CRC has an inherent resistance to immune checkpoint blockade, and several investigators have outlined the difficulties in applying immune checkpoint inhibitor therapy to a wider population of mCRC patients with MSS disease secondary to intrinsic resistance of MSS disease to immune checkpoint blockade [ 62 , 63 ]. Several toxicities and adverse events are associated with immune checkpoint inhibitors.…”

Advanced Nanotechnology for Enhancing Immune Checkpoint Blockade Therapy

“…More controversial findings were achieved in other malignancies, where the therapeutic efficacy of ICIs seemed restricted to subgroups of patients, such as in the case of esophagogastric tumors or breast cancer [ 8 , 9 ]. Finally, disappointing results were reported with the use of ICIs in cancers with immune-excluded or immune-desert microenvironments, including colorectal tumors where several combination strategies are under investigation in clinical trials [ 10 ].…”

Colorectal Cancer and Immunity: From the Wet Lab to Individuals

“…However, for mCRC, only few objective responses have been observed in unselected colorectal cancer patients. Long-lasting responses were only restricted to 4 to 5% of patients who presented tumors harboring microsatellite instability (MSI-H) and/or mismatch repair deficiency (dMMR) [ 12 , 13 , 14 , 15 ]. For this small subset of patients, the therapeutic scenario was nonetheless significantly changed thanks to the introduction of immune checkpoint inhibitors.…”

“…Indeed, MSI tumors are known for being highly intruded by tumor-infiltrating lymphocytes (TILs) such as CD8+ cytotoxic lymphocytes, Th1-activated cells that produce IFNγ, and CD45 RO+ T memory cells [ 8 , 16 , 17 ]. This phenomenon is explained by the hypermutated phenotype of these tumors, leading to high mutational burden (TMB) with highly immunogenic neoantigens as a consequence of a large number of deletions, insertions, and frameshift mutations accumulated during cancer cell replication [ 12 , 14 , 15 ]. The accumulation of tumor-associated neoantigens indeed favors the identification of cancer cells by the host immune system [ 18 , 19 ].…”