Page 42 - Read Online

Page 10 of 14 Bittoni et al. J Cancer Metastasis Treat 2018;4:55 I http://dx.doi.org/10.20517/2394-4722.2018.37

first one is a phase II study to evaluate the safety and abscopal effect of pembrolizumab after palliative RT
or ablation in pts with unresectable/recurrent pMMR metastatic colorectal cancer, who have received ≥ 2
[50]
standard therapies, with ORR in a non-targeted lesion as primary objective . After enrolling 26 patients,
pembrolizumab after RT or ablation resulted feasible with a tolerable safety profile, with one patient
achieving a partial response (PR) in non-irradiated lesions after RT (abscopal effect). The second one is
based on the hypthesis that combination of mFOLFOX6 and pembrolizumab may enhance immunogenic
cell death and improve outcome in patients with untreated, advanced CRC irrespective of MMR status.
After a median follow up of 24 weeks, clinical activity was seen in patients including those with proficient
[51]
MMR, with a DCR rate of 100% at 8 weeks .

A different strategy that is currently under evaluation to improve efficacy of immunotherapy in MSS/
pMMR CRCs is combination of histone deacetylase inhibitor and PD-1 inhibitors. Entinostat, an oral,
class I-selective histone deacetylase inhibitor is able to enhance anti-PD-1 activity by downregulation of
[52]
immunosuppressive cell types in the TME in models of renal and lung cancer.

Preliminary results of a phase II study of entinostat in combination with pembrolizumab have been recently
presented at ASCO 2018 annual meeting. Sixteen pretreated MSS/pMMR CRC patients were enrolled
and at data cut-off 6 patients remained on study (1 PR, 6 stable disease). The treatment showed acceptable
safety with common adverse events including fatigue (37.5%), arthralgia (18.8%), and increased alkaline
phosphatase (18.8%). These results can be viewed as promising, considering that have been obtained in a
[53]
patient population in which objective responses have not been reported with anti-PD-1 monotherapy .

In addition to immune strategies focused on PD-1/PDL-1 axis and CTLA4 and against cancer
immunotolerance, a series of different approaches (albeit still on the side of immunotherapeutic
approaches) are recently been investigated in CRC. T lymphocytes engineered to express chimeric antigen
receptors (CAR-T cells) have been tested for their potential role as therapeutic agents in CRC. In a recent
[54]
paper of Magee et al. , CAR-T cells expressing the human specific GUC2YC antigen variable fragment
were able to determine an increase of cytokine production and upregulation of markers of inflammation.
The cells were also able to induce a somewhat specific killing of CRC cells who did express GUC2YC,
whereas GUC2YC-deficient cells were spared. This was proven in in-vitro and in mice xenografts,
suggesting further development of CAR-T cells engineered to express this antigen.

[55]
However, in another paper of Huang et al. , it is also suggested that, albeit interesting, development
of CAR-T cells therapy for CRC patients should first be complemented by the addition of some forms
of treatment able to induce indoleamine 2,3-dioxygenase 1 (IDO1) downregulation. The authors have
examined the effects of CAR-T cells targeting EGFR variant III on CRC cell lines and correlated the
effectiveness of treatment on the basis of either IDO1 downregulation or normal expression on the basis of
the expression, in cell lines, of mir-153. In particular, due to the inhibitory effect on the expression of IDO1
of mir-153, the authors were able to find a significant correlation between CAR-T cells mediated killing of
CRC cells and high levels of expression of mir-153, thus suggesting that CAR-T cells treatment “per se” is
not enough to induce some meaningful tumor response.

Albeit manipulation of the mutational load of CRC patients is a mere piece of science fiction, it is well-
known that, for treatments that are focused on PD-1/PDL-1 axis, mutational load might represent the best
way to identify those patients who could benefit from this kind of strategy (more than the simplistic way of
[56]
assessment of patients as in microsatellite stable/unstable). In particular, in a recent paper of Fabrizio et al. ,
authors tested 6004 cases of CRC by matching MSI assessment (MSS or MSI-L vs. MSI-H) and estimation
of tumor mutational burden (TMB high or low). Authors found that the matching was not exactly perfect,
with 302 cases (5% cases) having MSI-H status and 301/302 (99.7%) MSI-H cases having TMB high status