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Page 12 of 16 Cidon. J Unexplored Med Data 2018;3:8 I http://dx.doi.org/10.20517/2572-8180.2018.03

vaccinia-CEA(6D)- TRICOM, with and without granulocyte macrophage colony-stimulating factor (GM-
[64]
CSF) in patients with CEA-expressing cancers . This study showed that this was safe but had limited
efficacy in selecting patients with stable disease and the duration of the response was of at least 4 months.
Another trial, phase II, assessed the efficacy of chemotherapy combined with a vaccine with canarypox virus
[65]
(ALVAC) expressing CEA and B7-1 (ALVACCEA/B7-1) .

Although 50% of the patients had anti-CEA-specific T cell responses and 40% of the patients showed
objective clinical response, no differences were detected between the two groups.

TroVax is a highly attenuated strain of vaccinia virus encoding the 5T4 protein (an oncofetal antigen and
[66]
a transmembrane glycoprotein highly expressed in colon cancer) that has become a good target . Small
clinical trials have shown that TroVax is active in metastatic colon cancer because it can lead to antibody
[66]
formation against the 5T4 antigen and the virus as well .
Oncolytic viral therapy
This technique uses a virus as an anticancer treatment which is able to destroy malignant cells without
hurting healthy tissue. The phase III OPTIM trial used a GM-CSF expressing variant of herpes simplex
virus 1 (HSV-1) and showed superior OS with an acceptable toxicity profile for unresected melanoma when
[67]
compared to to subcutaneous GM-CSF . This led to its approval but unfortunately for colon cancer there
[68]
are not available treatments yet . Pre-clinical research has shown that G207, herpes simplex virus type-1
[69]
with multiple mutations, is effective in five different colon cancer cells lines .
A multicenter phase I/II trial showed that four doses of a genetically engineered oncolytic herpes simplex
[70]
virus (NV1020) in liver-dominant metastatic colon cancer disease , through hepatic artery infusion,
followed by standard chemotherapy was well tolerated and achieved a median TTP of 6.4 months, OS 11.8
months and 47.2% were alive in one year.

Another trial, phase 1b assessed Pexa-Vec, an oncolytic virus used to treat refractory colon cancer patients
and showed stable disease in 67%. Unfortunately, this trial could not determine the maximum tolerated dose
of Pexa-Vec. Another phase I/II trial is testing Pexa-Vec oncolytic virus in combination with tremelimumab
in refractory colon cancer. This trial is still recruiting patients.

Other check points
There are other checkpoints targeted in early studies such as LAG3, OX40 and TIM3. The inhibition of
[71]
OX40 has shown good results in preclinical research and there is currently a trial recruiting patients with
metastatic colon cancer to be treated with an anti-OX40 (NCT02559024).

LAG3 is expressed on regulatory T cells and agents blocking LAG3 and PD-1 have shown an improvement
[72]
in survival in a MC38 colon cancer mouse model .
Adoptive cell therapy
Adoptive cell therapy uses ex vivo expanded tumor-infiltrating lymphocytes (TIL) against tumour antigens
and this strategy has shown good responses in melanomas. Most of KRAS mutations occur at codon 12
[73]
where glycin is changed to aspartic acid, called KRAS G12D and is present in 13% of colon cancers . In
[73]
2016 Vaughn et al. published a case showing tumour regression with the infusion of cytototoxic T cells
against the KRAS G12D.

Targeted chimeric antigen receptor T cells
This is an innovative therapy that uses engineered T cells expressing a chimeric molecule formed by the