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Bittoni et al. J Cancer Metastasis Treat 2018;4:55 I http://dx.doi.org/10.20517/2394-4722.2018.37 Page 9 of 14
[40]
bevacizumab when combined with conventional chemotherapy, researchers are trying to further enhance
the effect on the immune system by coupling anti-angiogenic treatment with immunotherapy and this
strategy might be particularly relevant for CMS4 tumors. Several clinical trials are investing whether
combination of bevacizumab with either immunotherapy alone or combined with targeted therapies and
conventional chemotherapy might show activity in this setting (NCT02873195, NCT02291289, NCT02876224).

Another key aspect of the TME of CMS4 tumors is represented by activation of TGF-β signaling. Using a
[41]
preclinical model of CT26 colon carcinoma cells, Triplett et al. showed that combining aOX40 antibodies
with an inhibitor of the TGF-β receptor (SM16) had a synergic action and elicited complete regression of
tumors. Targeting the TGF-β pathway with galunisertinib as monotherapy and in combination with anti-
PD-1 agents, induced anti-tumor immunity and tumor shrinkage also in a mouse model of mesenchymal
[42]
CRC . Based on these evidences, multiple TGF-β targeted therapies are currently in clinical trials.
CMS2 and CMS3 are considered as “cold” tumors, meaning that they lack immune cell infiltration. The
level of expression of immunosuppressive genes is low, thus suggesting different mechanisms of immune
escape. For example, the downregulation of MHC class I observed in these tumors, results in reduced
[43]
presentation of tumor-associated antigens . CMS3 tumors are frequently RAS mutated. In a recent study
[44]
by Lal et al. who used The Cancer Genome Atlas RNA-seq, KRAS-mutant CMS2 samples had reduced
infiltration of cytotoxic cells and neutrophils relative to CMS1 and CMS4 and to KRAS wild-type CMS2
samples. Deregulation of mitogen-activated extracellular signal-regulated kinase (MEK) pathway is
involved in carcinogenesis and maintenance of cancers. This pathway is physiologically activated by growth
factors, but in pathological conditions mutations of oncogenic proteins (such as RAS and RAF) can cause
the systematic activation of the MEK cascade. MEK inhibition with cobimetinib upregulates tumor major
histocompatibility complex-I expression, promotes intratumoral T-cell accumulation and enhances anti-
[45]
PDL-1 responses . In a recent phase Ib study presented at Gastrointestinal Cancer Symposium American
Society of Clinical Oncology (ASCO) 2018, sixty-six patients were enrolled to receive atezolizumab
in combination with Cobimetinib in metastatic or locally advanced CRC refractory to chemotherapy.
Preliminary data showed interesting results: OS was 10 months with durable responses in patients with
[46]
MSS or microsatellites instable-low tumors . Conversely, CMS2 tumors are usually characterized by
EGFR activation without mutations in downstream pathways (e.g., KRAS mutations). Cetuximab, an anti
EGFR monoclonal antibody, revealed a potential synergistic effect with monoclonal antibodies targeted to
CTLA4 and PD-1 antigens and in vivo studies, especially in patients with head and neck tumors and lung
[47]
cancer, are promising .

Other approaches that are being tested to improve immunotherapy response among CMS subtypes are
represented by cytokine treatment, cancer vaccination and passive immunotherapy with adoptive T cell transfer
[48]
or monoclonal antibody targeting tumor-associated antigens. Klein et al. recently evaluated carcinoembryonic
antigen (CEA)-IL2v (RG7813), an engineered IL-2 variant (IL-2v) with abolished IL-2Rα (CD25) binding fused to
an antibody targeting CEA to increase immune infiltration and activates NK and T cells both in the periphery
[49]
and within tumors. In two ongoing dose-escalation phase I studies, Tabernero et al. proved the antitumor
activity of CEA CD3 TCB (RG7802, RO6958688), a novel T-cell bispecific antibody targeting CEA on
tumor cells and CD3 on T cells, in 11% of adult patients with advanced CEA+ solid tumors who received
RG7802 as monotherapy and in 50% of patients to whom the antibody was given in combination with with
atezolizumab 1200 mg Q3W.

Likewise, other malignancies, combining immunotherapy with conventional chemotherapeutic strategies
or with radiotherapy (RT) might represent an useful and practical means to stimulate immune cell
infiltration and elicit immune response. To this purpose, clinical trials testing the combination of anti-
PDL-1/PD-1 treatment with RT or modified FOLFOX are ongoing (NCT02437071, NCT02375672). In the