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meeting (OS at 17.9 months and PFS at 3.9 months), whatever the chemotherapy regimen or targeted therapy
[40]
used (bevacizumab or anti-EGFR) .

Actually, immunotherapy is a prominent therapeutic approach in many cancers, such as melanoma, non-
small cell lung cancer, kidney and bladder cancer. However, significant advances have been made also in
CRC. A first study utilizing a CTLA-4 antagonist monoclonal antibody, tremelimumab, showed a possible
[41]
usefulness of immune checkpoint inhibitors in CRC, obtaining one 6-month durable response .
[42]
Then, in the phase II trial conducted by Le et al. , the clinical activity of pembrolizumab was evaluated
in three cohorts of patients: MSI-H CRC, MSI-H non CRC, and MSS CRC. The immune-related objective
response rate (ORR) and the immune-related 6-month PFS rate were 40% and 78%, respectively, in the
dMMR CRC patients, 0% and 11% in the pMMR CRC patients. These findings currently are being evaluated
in the KEYNOTE-177 phase III trial in patients with dMMR metastatic CRC who have been randomized to
treatment with pembrolizumab vs. standard therapy.

In Checkmate 142, nivolumab alone and the combination of nivolumab + ipilimumab were evaluated in
patients with metastatic CRC, with or without MSI. Seventy patients with MSI-H CRC were enrolled and
treated with nivolumab monotherapy (3 mg/kg every 2 weeks). At the preliminar presentation of the trial
results, of the 47 patients which had at least 12 weeks of follow-up, 26% had an objective response while 30%
had stable disease, with disease control rate of 55%. In the update published on Lancet, 23 of 74 patients
achieved an objective response (ORR 31%) and 51 of 74 patients had disease control for 12 weeks or longer
[43]
(DCR 69%) . By the use of combination therapy (nivolumab 3 mg/kg q2 week plus ipilimumab 1 mg/kg
q3 week × 4 doses, followed by nivolumab monotherapy), investigator-assessed ORR was 55%, and disease
[44]
control rate for ≥ 12 weeks was 80% . In this heavily pre-treated population, 12 months overall survival was
73% and 85% with monotherapy and combination therapy respectively. Grade 3 and 4 drug related adverse
events (AEs) were reported in 25 patients treated with nivolumab (20%) mainly asymptomatic increasing of
amylases and lipase: only 5 patients (7%) stopped the treatment due to toxicities. In the combination group,
grade 3 and 4 AEs were reported in 32% of patients: 15 patients (13%) discontinued treatment because of
study drug-relates AEs.

All these data supported the benefit of immunotherapy in MSI-H CRC, and for this reason FDA approved
the use of nivolumab and pembrolizumab in patients with unresectable or metastatic MSI-H and dMMR
CRC, that have progressed after previous treatment.

Similar results were not reached in MSS CRC, in fact in the pivotal pembrolizumab study, no response was
achieved, with very poor PFS and OS, as subsequently confirmed in other trials [45,46] [Table 1].

There are several combination clinical trials and novel immunotherapeutic strategies under active
investigation for metastatic CRC [Table 2].

STRATEGIES TO CONVERT AN IMMUNE IGNORANT TUMOR INTO AN INFLAMED ONE
There are mainly 3 different tumour immune phenotypes [Figure 1]:
1. Highly immune-infiltrated tumours with favourable immune microenvironment, enriched of Th1-type
functional TILs;
2. Highly immune-infiltrated tumours with unfavourable tumour microenvironment with active
angiogenic and immunosuppressive pathways;
[47]
3. Poorly immunogenic tumours with minimal immune cell infiltration .