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Page 10 of 16 Cidon. J Unexplored Med Data 2018;3:8 I http://dx.doi.org/10.20517/2572-8180.2018.03

in terms of ORR and PFS at 6 months.

LYMPHOCYTE-ACTIVATION GENE 3 (CD223)
Cases of MSI-H show shorter prognosis if they are found to be positive for lymphocyte-activation gene 3
[4]
(LAG-3) . pMMR liver metastatic colon cancer seems to show higher sensitivity to checkpoint inhibitors than
proficient original cancers. LAG3 and PD1 regulate autoimmunity and if blocked at the same time, a stronger
[46]
[45]
anti-tumour immune response is seen. Sometimes this event produces autoimmunity . Zhou et al. have
reported that blocking LAG3 stimulates tumour-infiltrating T-cell responses of these patients and therefore
this could be a new target for liver metastatic colon cancer.

THERAPEUTIC VACCINES
Cancer vaccination has been used in several cancers to obtain an anti-cancer immune response, remove
the cancer and provide maintained surveillance to protect against a recurrence or progression. There are
different vaccines used in colon cancer such as autologous, peptide, viral vector and DC [Table 2].

Autologous vaccines
These use malignant cells taken directly from the patient’s cancer. Whole tumour cell vaccines have shown
reduced clinical activity as most antigens are present in normal cells and the generated immune response is
[47]
not specific to cancer cells .
A randomized phase III trial with a patient-specific vaccine using autologous cancer cells combined with
[48]
BCG vaccine was carried out. Patients were randomized to two arms, surgical resection plus the vaccine
[48]
vs. resection only. DFS and OS were not significantly different at 7 years but longer follow-up did show
[49]
statistically significant benefits in all endpoints including DFS and OS but only in stage II .
There are other ways to increase the immunogenicity of autologous vaccines by using autologous tumour cell
vaccine modified by a non-lytic, low pathogenic strain of the Newcastle disease virus (NDV).

A phase II trial recruited 23 patients to receive tumour cells incubated with NDV. The results showed a
[50]
reduction in recurrence rate of 61% compared to 87% in a historical matched control group . A phase III
trial randomized patients with stage IV colon or rectal cancer to receive either NDV-infected autologous
[51]
tumour cell vaccine group or to control group and did not show any differences in OS, however, a
subgroup analysis demonstrated a significant improvement in colon cancer compared to rectal cancer.
Autologous vaccines have not changed significantly the clinical practice due to low activity, however, some
evidence could support them in colon cancer but not in rectal cancer.

DC vaccines
[52]
DCs are powerful antigen presenting cells that play an important role in promoting immune responses .
These cells will stimulate naïve T lymphocytes responses and also memory T cells responses and they are
key controllers of anticancer responses by releasing co-stimulatory signals and producing cytokines. DC
[53]
based vaccines have been under investigation for long time . These have been prepared by harvesting DCs
from patients, loading them ex vivo with neoplastic antigens, tumour RNA or whole malignant cells and
once these are activated, the DC vaccine is re-infused into the patient with the aim getting a tumour specific
[53]
immune response .
Some of these vaccines have used CEA as tumour antigen, as this is present in the majority of colon
cancers. Early evidence has shown that these vaccines are safe and effective in promoting a specific tumour
[54]
response but unfortunately there are not phase III trials to support this. A recent phase II study has
[55]
compared autologous tumour lysate DC vaccines with best supportive care only and reported that this