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Page 8 of 17                     Spallanzani et al. J Cancer Metastasis Treat 2018;4:28 I http://dx.doi.org/10.20517/2394-4722.2018.31

               combination of atezolizumab and cobimetinib or regorafenib has completed the accrual and its results are
               eagerly awaited.


               Another strategy to inflame these “cold cancers” could be enhancing T cell infiltration, typically poor in
               these tumors. Histone deacetylase (HDAC) inhibitors like romidepsin (preclinically tested for this capacity)
                                                                                                 [54]
               have been actually combined with anti-PD1 therapy in a phase I/II trial currently ongoing in CRC .
               Another option could be the use of BITEs (Bispecific T cell engager) that bind the CD3 subunit of the T cell
               receptor and a tumor specific antigen.

                                                         [55]
               Interesting results from preclinical experiences  lead to a phase I trial with CEA-CD3 TCB (RG7802,
               RO6958688). CEA-CD3 TCB is a novel T-cell bispecific antibody targeting CEA on tumour cells and CD3 on
                                                                                                       [56]
               T cells increasing intratumoral T cell infiltration and activation and enhancing the PD-L1/PD-1 pathway .
                                                                           [57]
               The phase I trial results, presented at ASCO 2017 by Tabernero et al. , suggested antitumor activity in
               monotherapy and enhanced efficacy in combination with atezolizumab in patients with advanced CEA+
               solid cancers with manageable safety profile.

               COMBINATIONS WITH RADIOTHERAPY
               Radiotherapy determines cell death in targeted lesions inducing local and systemic immune-mediated anti-
                                         [58]
               tumour effects. In 1953, Mole  proposed the term “abscopal effect” referring to the effects of ionizing
               radiation at a distance from the irradiated volume but within the same organism. Almost 50 years later, the
               role of the immune system in this “off target” effect has been settled. RT may affect antitumor immunity
               by enhancing antigen presentation by upregulation of major histocompatibility complex class I (MHC-
                                                                                      [59]
               1) expression of malignant cells and upregulation of tumor-associated antigens . The clinical use of
               immune checkpoint inhibitors has greatly increased the number of abscopally responding patients. In
                                         [60]
               a preclinical trial, Park et al.  achieved complete regression of primary tumour and partial response
               in distant metastases via abscopal responses with combination of radiotherapy and anti-PD1. At ASCO
               2016, preliminary results of a phase II trial evaluating the abscopal effects of pembrolizumab after liver
               radiofrequency ablation or external beam radiotherapy had been presented. Tolerable safety profile and a
                                                                                          [61]
               partial response in non-irradiated lesions over 23 patients treated have been demonstrated . A phase II trial
               investigating the efficacy of durvalumab-tremelimumab in combination with radiotherapy in patients with
               liver limited disease is underway (NCT02888743).

               Trials with long-course chemoradiation in combination with PD-1 inhibition in locally advanced rectal
               cancer are still ongoing and so answers about this approach should be available in the next few years
               (NCT02948348, NCT03038477).


               IMMUNOTHERAPY COMBINATIONS
               The clinical activity of epacadostat (IDO-inhibitor) alone appears limited but combination with
               pembrolizumab in melanoma patients reported ORR of 58% [62,63] . Actually epacadostat has been investigated
               in combination with pembrolizumab and azacitidine in refractory MSS CRC.

               Also cetuximab, an anti-EGFR antibody actually approved for treatment of pan-RAS wt colorectal cancer,
               demonstrated a T-cell response and antigen liberation in HNSCC; in mCRC patients treated with cetuximab
                                                               [64]
               a relevant intratumoral T-cell infiltrates has been shown . For these reasons, an ongoing phase I-II trial is
               examining the role of cetuximab-pembrolizumab combination in mCRC.
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