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

[5]
MHC molecules in cancer and transplantation , they have been considered highly artificial in many ways.
For instance, a high dose of carcinogen may result in cancer in a given strain of syngeneic mice in a short
time. Transplantable tumors developed in such a way have been maintained in vitro and in vivo intermittently
for years. When these tumor cells were used in transplantable models by injecting cells into young, syngeneic
animals, thereby circumventing the influences of environmental and genetic factors that are indeed operative
in human situations, results obtained from these studies have only most remote relevance to cancers in
humans. Thus, these transplantable tumors are simply not analogous to clinical cancers and the conclusions
drawn from them are less likely to be applicable to human cancers.

Early immunotherapy experiments produced a dogma that immunological manipulations could only
8
work when the tumor cell mass was imperceptible (< 10 cells), which presented real problems for clinical
immunotherapy, because the tumor mass at clinical diagnosis or after surgery is at least two orders of
8
magnitude greater than 10 cells. Despite the obvious difficulties with experimental models and translation
to humans, clinicians began large-scale immunotherapy trials in the 1970s. The results of initial, small,
uncontrolled trials were often reported as positive. However, when large, randomized, controlled studies
were conducted to confirm the efficacy of a particular immunotherapy regimen in a particular type of cancer,
some of the controlled studies were positive and but most yielded marginal or negative results. Therefore,
overall cancer immunotherapy developed a bad image among physicians, chemotherapists in particular, by
the end of the 1970s.

Looking back, there were a number of reasons that could be considered for the failure of cancer
immunotherapy to establish itself as a major treatment modality. One of the reasons was a lack of definition
for highly purified immunotherapeutic agents. For instance, any of the nonspecific approaches using complex
chemicals and poorly defined bacterial and viral extracts to stimulate the immune response of patients often
made the interpretation of results difficult. Consequently, there were problems in reproducibility of the
results generated even by members of the same research group. Thus, molecular definition of the molecules
in question, such as immune modulators, lymphokines/cytokines, tumor antigens and antibodies, became
the hot subject for many investigators to pursue. Another reason was the general lack of understanding of
[6]
the immune responses in cancer patients then, such as the rule of MHC-restriction , definition of T cell
[7]
receptor, and interactions among components at the region of immunological synapse . Immunotherapy is
not an appropriate term for the modern use of biologic substances and BRMs in medicine. Biological control
mechanisms should be envisioned on a much broader basis than the immune system. Immunotherapy
remains a subcategory of biotherapy, but growth and differentiation (maturation) factors, cytokines,
angiogenic inhibitors, and recently identified immune checkpoint inhibitors, and synthetic derived molecular
analogues are indeed much broader than immunotherapy.

Certain specific developments over the past thirty years led to biotherapy becoming the 4th modality of
[8,9]
cancer treatment . Advances in molecular biology have given scientists the greater capacity to clone
individual genes and produce large quantities of highly purified gene products as medicines. The proteins
resulting from the cloned genes have a level of purity and homogeneity on a par with drugs and can be
produced in unlimited amounts. They can be analyzed alone or in combination with other gene products as
to achieve their optimal effects in cancer biotherapy. Additionally, progress in genomic and gene mapping
science, nucleic acid sequencing and translation, protein synthesis, isolation and purification of the biological
products, as well as in mass culture of cells with the use of bioreactors has given the scientific community the
power to identify of new biological molecules, modify nucleic acids and proteins at the nucleotide or amino
acid level to manipulate, optimize their biological activity, and use clinically. The elucidation of the human
genome and the encoded products have considerably broadened the opportunities for the advancement of
cancer biotherapy. Along with tumor cell vaccines and non-specific immune stimulators such as bacillus
Calmette-Guerin, adoptive cell therapy and monoclonal antibodies (mAbs) are two popular biotherapeutic
approaches used clinically. Some of their specific components such as chimeric antigen receptor (CAR)-T