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Page 6 of 8 Bourinbaiar et al. Hepatoma Res 2020;6:2 I http://dx.doi.org/10.20517/2394-5079.2019.25

Hepcortespenlisimut-L represents an entirely novel class of immunotherapy that has no analogs among
approaches being developed currently [12,13] . This approach is radically different from the checkpoint
inhibitor class of immunotherapies, aimed to revive and keep the “weakened” immune system active.
This approach is also different from classical injectable cancer vaccines that incorporate tumor antigens
[15]
[14]
common in this type of cancer, such as AFP , Glypican-3 expressed in > 80% of HCC , or other multi-
[16]
epitope tumor peptides . Considering that checkpoint inhibitors have low clinical benefit and single-
or few-antigen vaccines have not delivered the expected success, it is clear that new approaches are still
needed.

Scientists at Arizona State University recently identified more than 200,000 cancer neoantigens, which
[17]
could lead to the development of broad-spectrum cancer vaccines . V5 inherently incorporates all
circulating antigens from pooled blood of HCC patients, including tumor unrelated immunogens such
as viral hepatitis antigens and very large number of alloantigens, which are not necessarily pathogenic.
It is clear that the identification of these antigens is a task posing enormous challenges. Taking aside the
academic pursuit of finding the mechanism of action, this challenge is not very important to a patient who
needs to be treated immediately, not after the putative antigen(s) are identified.

It is clear that oral delivery route is advantageous since this route eliminates the undesirable cross-
reactivity plaguing injectable vaccines. Another advantage associated with transmucosal passage of
antigens is induction of the immune tolerance - a phenomenon we experience on a daily basis when we
ingest, for example, food, which is composed of non-self, foreign antigens that would normally provoke
[18]
violent immune reaction if delivered parenterally . The gut immunity has evolved and differs from the
systemic immunity by this critically distinct trait. We would not exist as a species if we did not develop the
oral tolerance.

Our flow cytometry data, despite a limited number of studied parameters, suggest that the immune
tolerance is not a passive state akin to immune anergy, but rather it is a very active process with the
phenomenal activation of effector cells, as demonstrated by several-fold increase of immune activation
markers such as Ki67 and CD69 in as little as 48 h. At the same, time this process displays pronounced
anti-inflammatory activity, as revealed by ten-fold decrease of TNF-α, and no effect on IL-2 expression
- the hallmark of T-cell activation. Increase in IFN-γ output in CD4 but not in CD8 T cells was another
unanticipated result. Thus, the exposure to a pool of antigens derived from a tiny amount of peripheral
blood of patients with HCC produced results that have not been previously described in the literature.

The field of immunotherapy, particularly for oncology, is evolving rapidly, bringing new surprises daily.
[19]
Recently, a study was published in Nature by Alspach et al. , in which they gave more weight to the role
of helper CD4 lymphocytes in immuno-oncology over the usual culprit, i.e., CD8 killer cells. Whether V5
more affects CD4 rather than CD8 cells remains to be established; it is likely that both subpopulations are
required, and that other subsets of immune cells are also critically involved [20,21] .

Our investigation of hepcortespenlisimut-L is in its early stage and we are sure we will make more
surprising discoveries down the road. Besides the profound influence on the immune response, which
is usually expected from cancer vaccines, we see very clear clinical benefits in terms of improved liver
function and decrease in AFP levels, which we have shown to be correlated with tumor shrinkage. We have
successfully used V5 since 2010 in hundreds of patients with HCC and we are confident that the outcome
from this Phase III trial will be consistent with the results of the Phase II retrospective study published in
[7]
2017 . In conclusion, our experience in dealing with V5 and patients with HCC receiving this simple to
use immunotherapy is supported by the present observation. Further studies will shed more light as to the
mechanism of action and extent of the clinical benefit.