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Cidon. J Unexplored Med Data 2018;3:8 I http://dx.doi.org/10.20517/2572-8180.2018.03 Page 9 of 16

of IFN gamma in several neoplasias and this produces a reduction in immune response through a reduction
in the levels of tryptophan in the neoplasia and lymph nodes. Finally this creates immunotolerance through
inactivity of T cells and dendritic cells (DCs).

Basic studies have considered that blocking IDO delays tumour progression, stimulates DC vaccines and
shows synergism with chemotherapy.

The d-1-methyl-tryptophan (d-1-MT) is an IDO inhibitor which has been chosen for phase I trials.

IDO is upregulated during inflammation and this transforms the microenvironment in immunosuppressive.
[40]
In colon cancer patients, IDO is linked to reduced CD3+ infiltrating T cells and shorter prognosis .
Epacadostat is an IDO inhibitor which has been recently tested in advanced solid tumours. Fifty-two patients
received epacadostat with escalating dosages and continued on this drug until progression or significant
side-effects was confirmed. Dose-limiting toxicity (DLT) was detected with 300 mg twice daily (pneumonitis
post radiotherapy) and with 400 mg twice daily (asthenia). Main toxicities were fatigue, gastrointestinal side
effects, abdominal or back pain, cough, and breathlessness. On this treatment, seven patients showed long
stable disease lasting ≥ 16 weeks.

Authors concluded that this drug is generally well tolerated and has caused the maximal blockage of IDO
if administered at ≥ 100 mg twice daily and threre are some ongoing trials evaluating epacadostat with
[41]
different immunomodulatory agents . Multiple other trials are ongoing such as ECHO-206 which combines
epacadostat with azacitidine and pembrolizumab in cases diagnosed with advanced solid neoplasias
(NCT03182894). This trial is active but not recruiting.

Colony-stimulating factor-1 receptor inhibitors
The macrophage colony-stimulating factor 1 receptor (CSF-1R) is a target for CSF-1 and seems to be in
charge of the macrophages’ function. Preclinical studies suggested that blocking CSF-1/CSF-1R shifts
[42]
monocytes population from promoters to tumour suppressors .

Pexidartinib is a CSF-1R inhibitor which is under study combined with durvalumab in a phase I trial which
includes colon and pancreatic cancer patients (NCT02777710). This trial is recruiting patients.

Anti-EGFR agents
Pembrolizumab is also under study in combination with cetuximab (NCT02713373) as this one has
demonstrated in preclinical studies, to stimulate cellular cytotoxicity and to produce EGFR-specific T-cell
response and antigen dissemination in head and neck cancers . In metastatic colon cancers treated with
[43]
different chemotherapies, those who receive anti-EGFR treatments show significant intratumoral T-cell
[44]
infiltrates. The primary end points for this trial are ORR and PFS .

Cetuximab is a chimeric IgG1 anti-EGFR monoclonal antibody. The Phase Ib/II study combining
pembrolizumab and cetuximab tested the safety and efficacy of this combination in metastatic colon cancer.
Patients with RAS wild type metastatic colon cancer after progression on one previous line of treatment
2
were included and received pembrolizumab every 3 weeks at 200 mg and cetuximab at 400 mg/m loading
dose, followed by 250 mg/m weekly. Nine patients recruited onto the phase Ib did not show any dose
2
limiting toxicities and most frequent side-effects were acneiform rash, xerosis, hypomagnesemia, vomiting
and fatigue. Grade 3 and 4 toxicities were not frequent so authors concluded that this combination was well
tolerated and currently the phase II is running and will recruit 33 patients to test the efficacy of this regimen