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Page 2 of 10                                  Liao et al. J Cancer Metastasis Treat 2018;4:3  I  http://dx.doi.org/10.20517/2394-4722.2017.63


               modulatory properties, as well as direct cytolytic, cytostatic growth-inhibitory, or maturational effects
               on tumor cells. This is, in part, the reason why cancer biotherapy provides a much broader spectrum of
               antitumor action than cancer immunotherapy.

               This article is an updated version of the commentary entitled, “Cancer biotherapy: more than
                                       [2]
               immunotherapy” by Oldham  published in Cancer Biother Radiopharm 2017;32:111-4.
               Biotherapy of cancer can be effective against clinically apparent, even bulky cancer, and treatment should not
               be restricted to situations where the tumor mass is imperceptible. Thus, a clinical trial designed for cancer
               biotherapy can be similar to other modalities as long as one measures both the specificity and activity of
               biological response affected by these approaches. Nevertheless, the specificity of biotherapy often requires
               individualized testing and therapy, one important aspect of biotherapy that is different from chemotherapy.

               It should be stated at this onset that the literature addressing the concepts highlighted in this paper is
               immense and will not be exhaustively reviewed here. Instead, we provide a commentary on immunotherapy
               vs. biotherapy of cancer from both the historical and future perspectives with an overview of the current
               trends in research focusing particularly on recent cellular, vaccine and targeting strategies that have real
               potential for patients.



               HISTORICAL PERSPECTIVES
               The use of chemical and biological compounds to modulate biological responses has been under active
               investigation for more than five decades. While various chemical, bacterial extracts and viruses have been
               found to modulate immune responses in experimental animals, and to a much less extent in humans, these
               nonspecific immune modulators have not been highly effective as therapy for human cancers. Molecular
               biologists have developed many new technologies in the isolation of genes and their subsequent transcription
               and translation into protein production, yielding high levels of purity. These processes make virtually
               unlimited quantities of purified biological products available for both experimental and therapeutic use. In
               vitro assays of biological activity (bioassays or functional assays) were intensely developed and used to define
               and quantify the activity of a given biological molecule in the 1980s, and the paradigm of cancer research
               and therapy has changed substantially. These assays, such as flow cytometry, enzyme-linked immunosorbent
               assays, immunoprecipitation, immunoblotting, immunohistochemistry, human leukocyte antigen (HLA)
               typing, epitope prediction, tetramer assays, detection of circulating cancer cells, cytotoxicity assays, CRISPER
                          [3]
               gene-editing , humanized mice and liquid biopsy have allowed the precise determination of identity, activity
               and specificity of these molecules or cells as part of cancer therapeutics. Some of them also provided the
               monitoring assays for the patients before, during and after treatment.

               Since the early 1970s, inbred or syngeneic animals were used experimentally because it was realized that the
               variability in cancer behavior could be due to the differences in major histocompatibility complex (MHC)
                                    [4]
               among out-bred animals . Therapeutic manipulations using these syngeneic animals with transplantable
               tumors met with challenges, since they were very different from animals with naturally occurring cancers.
               Thus, the relevance of these animal models for cancer in humans was questionable. As opposed to
               transplantable cancers arising from carcinogenic stimuli in a particular organ starting from one cell or a
               few cells, naturally occurring cancers have been gone through a prolonged period of latency, before they are
               pathologically diagnosed as malignancies. In humans, these initial tumor foci may be in a benign or dormant
               state for various lengths of time ranging from 1% to 30% of human lifespan before there is a clinical evidence
               of cancer. Dissemination of these cells from the primary lesion may occur anytime during the development
               of the primary tumor. Subsequently, growth and metastasis may occur over periods of months to years
               from the primary or secondary lesions. Although we have learned a great deal about the basic biology of
               tumorigenesis and cancer pathophysiology from experimentally induced cancers, such as the importance of
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