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substances that are often active in association with the immune system. The diversity of the immune system
is best understood by clinical immunologists and cell biologists who are well suited to assist in the translation
of these approaches to the clinic. This concept was first put forwarded in 1977 by the Nobel laureate Sir Peter
[30]
Medawar .
“The cure for cancer is never going to be found. It is far more likely that each tumor in each patient is going
to present a unique problem for which laboratory workers and clinicians between them to work out a unique
problem.”

Cancer classification and biology have largely been embedded in the minds of pathologists and transmitted
through textbooks of medicine to medical students who become clinicians at later dates. These concepts
classify cancers categorically according to the tissue origin and biological features. Despite the laboratory
observations that phenotypic analysis and even the genotype of cancer biology confer great diversity within
cancers of same histological type, we continue to evolve new therapeutics as if all breast cancers, all lung
cancers, and all colorectal cancers are similar. However, this is fundamentally and biologically incorrect.
There has never been a technology that allowed cancer biologists to understand cancer on an individualistic
basis. Now it is possible to generate antibodies and type tumors specifically, leading to the generation of
[31]
cocktails of antibodies or immune conjugates to respond to diversity inherent in cancer biology . Below are
the most recently developed innovative strategies to cancer biotherapy which are listed under the following
three subtitles, each being involved with the cells and agents mentioned in the “Historical Perspectives”
section, namely CAR-T cells and immune checkpoint inhibitors, anti-PD1 and anti-PDL1.

Immunotargeting cancer stem cells and metastasis
Metastases, often resistant to conventional therapy, are the major cause of death from cancer or the treatment
failure. In most cancer patients, metastases have already taken place at the time of diagnosis. Most recently,
the successful identification of two cellular entities, namely cancer stem cells (CSCs) and metastatic cancer
stem cells (mCSCs) with the expression of CXCR4 [21,32] , both constituted very small proportions of cells
within a given tumor, has stimulated a new direction for investigations as to how to eradicate or control of
these two cell types. Of note, the CXCR4-positive mCSCs with metastatic potential constitute much lower
numbers than the tumoroigenic CSCs in the given tumor [32,33] . This is because both entities are considered
the root causes of cancer (tumorigenesis), with the latter being the cause of both tumorigenic and metastatic
activities. The predominant subpopulations of cells within a tumor belong to so called non-CSCs which
are heterogeneous with more than one differentiated phenotype. These non-CSCs are believed to be more
sensitive to be killed by conventional therapies, such as radiation and chemotherapy. Expression of surface
antigens such as ALDH, CD44, EpCAM, or CD133, which distinguish CSCs from non-CSC tumor cells and
normal counterpart cells, together with CSC immunogenicity and relatively low toxicity of immunotherapies,
makes immunotargeting of CSCs/mCSCs a promising approach for cancer biotherapy [32-35] . The approaches
to target and eliminate CSCs include using NK, DCs, T cells, mAbs, and bispecific antibodiess. A case in
point, Her2- specific T cells from glioblastoma multiforme (GBM) patients were constructed by genetic
[36]
transfer of Her2-specific CAR . These Her2-specific CAR-T cells showed cytotoxicity against Her2-positive
targets in vitro and secreted immunostimulatory Th1 cytokines. The Her2-specific CAR-T cells were able to
kill in vitro autologous CD133-positive GBM stem cells expressing Her2, which were found to be resistant
to current conventional therapies. Adoptive transfer of Her2-specific CAR-T cells prepared in such a way
resulted in prolonged regression of autologous orthotropic GBM xenografts [36,37] . These findings confirm the
Her2-specific CAR-T cells targeted and eradicated Her2-positive tumor cells and their putative cancer stem
[38]
[39]
cells. Furthermore, NK and CIK with or without DCs were found to effectively kill stem-like cancer
+
cells. Incidentally, synergistic targeting of breast CSCs by human gdT cells and cytotoxic CD8 T cells in
[28]
combination has also been reported . Further technical refinements along this line of investigations are
currently underway in a number of laboratories.