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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