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Page 6 of 10 Liao et al. J Cancer Metastasis Treat 2018;4:3 I http://dx.doi.org/10.20517/2394-4722.2017.63

We may have to design the strategies of targeting metastasis at two levels, one to prevent metastasis of
the primary tumor by targeting CSCs, and another to target the established metastasis through CSCs and
mCSCs. In addition to various cell-based immunotherapies such as CAR-T cells, much of in vitro and in
vivo studies or clinical trials in the identification of various biological agents including a number of small
molecules and botanical nutraceuticals. For example, being a potent BRM itself, withaferin-A, a withanolide
extracted from the Indian winter cherry Withania somnifera, was found to be able to selectively block certain
signaling pathways involved in the proliferation/migration/apoptosis/angiogensesis/antioxidant in the two
types of CSC entities [34,40] . In contrast, those of the non-CSC and normal cell counter parts were relatively not
affected by withaferin-A. Many botanical and many other biological and synthetic compounds are currently
being under active investigation with regard to their targeting potentials on CSCs and/or mCSCs of a variety
of tumors.

Immunotargeting the tumor microenvironment
Investigation into targeting the tumor microenvironment is also becoming one of the major cancer
biotherapeutic strategies in the recent years [41,42] . The tumor microenvironment includes infiltration of
carcinoma-associated fibroblasts such as myofibroblasts and mesenchymal stem cells, infiltration of
inflammatory cells such as T cells, macrophages, DC cells, NK cells, myeloid derived suppressor cells,
regulatory T cells, and infiltration of blood cells such as blood endothelial cells and lymphatic endothelail
cells, and non-cellular components for remodeling of extracellular matrix, etc. The recognition of the
importance of tumor microenvironment in cancer progression has indeed led to a shift from a cancer-
centered view of cancer development to the concept of a complex cancer microenvironment or an ecosystem.
In a tumor microenvironment, various cellular and molecular components are as influential as cancer cells
[41]
themselves for cancer progression including dissemination . One feature of such a microenvironment is
that minor changes in a single component noted above may cause a reorganization of the whole system.
Consequently, the interference with any element of the tumor microenvironment provides an opportunity
to tip off the balance of the ecosystem or counteract the cancer progression. The use of an inhibitor of
[42]
checkpoint molecules, namely humanized mAb anti-CTLA-4 or anti-PD1 [43,44] , or CAR-T cells in
combination with chemotherapy leading to some encouraging clinical results may therefore be considered as
the successful stories of targeting the tumor microenvironment.

Neoantigen/RNA mutanome vaccines
Clearly, T cells can be generated, induced and manipulated in a similar way a mAbs for specific cellular
therapy [20,30] . Surely enough, thanks to the cutting edge technologies of prediction and identification of target
epitopes for peptide design, very impressive clinical results was recently obtained by two groups, Harvard
Medical School, Boston, USA and Biopharmaceutical New Technologies corporation/medical Center of
[46]
[45]
Gutenberg University, Mainz, Germany, using personalized neoantigen and RNA mutanome vaccines
respectively, for patients with melanoma. A few months after vaccination, some of these patients achieving
partial responses found to have recurrent disease were treated with anti-PD1 therapy, and encouragingly
[45]
experienced complete tumor regression . The personalized vaccine therapies in both studies could induce
de novo T-cell clones that reacted with multiple individual-specific neoantigens or mutated gene products,
and recognized endogenously processed antigens, and hence autologous tumor cells. Such induced
immunogenicity could therefore have better chances of targeting a diversity of cancer clones per patient
with a high response rate, addressing tumor heterogeneity as well as minimizing the tumor escape by loss
of antigen. These two innovative studies with different preparations of vaccines again demonstrate exciting
examples of precision oncology/medicine.

IMMUNOTHERAPY IS INCLUDED IN BIOTHERAPY
Biotherapy is constituted more broadly to include all the factors described above. To take advantage of
the opportunities available through biotherapy, major structural changes are necessary in our system