Page 14 - Read Online

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.