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Spallanzani et al. J Cancer Metastasis Treat 2018;4:28 I http://dx.doi.org/10.20517/2394-4722.2018.31 Page 9 of 17

OTHER STRATEGIES TO ENHANCE THE IMMUNOTERAPY EFFECT
[65]
Other strategies are actually ongoing to enhance the response to immunotherapy .
MGN1703 is a DNA-based Toll-like receptor that acts as an immunomodulator with immune activation in
[66]
heavily pre-treated patients with mCRC in the phase II IMPACT trial in maintenance setting . Patients
who had completed first line standard chemotherapy + bevacizumab were randomly allocated to lefitolimod
or placebo. There was a statistically significant better PFS in the experimental arm from start of induction
[67]
therapy with the greatest benefit for patients with relatively low tumour burden . Data on the use of
MGN1703 (lefotolimod) as switch maintenance in patients with mCRC responding to first line chemotherapy
are awaiting (Impala phase III trial).

In the perioperative liver-limited disease setting, the role of immunotherapy in association of chemotherapy
was evaluated for the first time in 1996: a preoperative injection of IL-2 in patients with DUKES D tumours
neutralized surgery-induced immunosuppression with improved overall survival due to postoperative mean
numbers of T lymphocytes, natural killer cells and activated lymphocytes significantly higher in IL-2-treated
[68]
patients than in controls . Results from ongoing trials with check-point inhibitors also in this setting are
awaited.

In the CRC prevention setting, the role of immunotherapy alone or in combination with chemotherapy is
under evaluation. Vaccination is by far the first approach evaluated. Based on a MUC-1 vaccination clinical
trial that enrolled 39 patients and suggested the presence of immunosuppressive mediators in premalignant
[69]
stages , a multicenter randomized phase II trial for testing the efficacy of this vaccine is actually ongoing
(NCT02134925). Therapeutic KRAS mutated vaccines have been tested in preclinical trials for advanced
[70]
tumors .
Combinations of immune-modulating agents and chemopreventive drugs have been tested in preclinical
[71]
studies . The synergic effect of combining a non-steroidal anti-inflammatory drug (NSAID) with an
immune checkpoint inhibitor is supported by preclinical data: aspirin induced upregulation of PD-L1 and
[72]
PD-L2 expression .

[73]
In a trial by Zelenay et al. , the combination of COX-inhibitor and PD-1 inhibitor, was effective in
eradicating BRAF-mutated melanoma neoplastic cells in mice with a significant increase in IFN, CXCL10,
IL12 expression as immune-stimulating factors.

There are a lot of exogenous and endogenous factors (collectively called exposome) which are able to
influence the development of CRC. However, for a comprehensive evaluation of tumor immunity, both
the neoplastic cells and the immune system need to be deeply analyzed. Immune cells analyses in the
tumor microenvironment have not been integrated into experimental immunological studies. In this
regard, molecular pathological epidemiology (MPE) offers the opportunity to a multilevel research using
bioinformatics and omics technologies to integrate immunology into population health sciences, providing
a deeper understanding of the interaction between tumor, exposome and immune system and offering new
[74]
insights for the development of intervention strategies, thus moving towards the era of precision medicine .
For example, the relation between microbiota and efficacy of chemotherapy and immunotherapy has been
extensively evaluated in experimental studies across various malignancies [75-78] . Analysis of microbiota can
[79]
be easily conducted by using oral swab or stool and integrated into immunology-MPE research .

[80]
Routy et al. observed the negative impact of antibiotics assumption during immunotherapy in terms
of ORR, PFS, OS in patients with NSCLC, renal cancer, urothelial cancer. To confirm the hypothesis