Page 93 - Read Online

Liao et al. J Cancer Metastasis Treat 2018;4:3 I http://dx.doi.org/10.20517/2394-4722.2017.63 Page 7 of 10

of translation of developmental therapies from a concept to the laboratory and then to the clinic. We
cannot afford to develop biological substances in a protracted, expensive, unidimensional manner of
drug development. We have a large number of biological substances, and the current system of access and
opportunity for patients, the system of funding research, our method of government regulation, and our
reimbursement system for the developmental therapies must undergo major structural changes. We are now
faced with the reality of many more opportunities for effective cancer biotherapy than the mechanisms by
which these opportunities can be tested and brought into clinical reality.

Development of new therapeutic programs have functioned under a format in which a new drug is brought
to the clinic through phase I clinical trial for toxicity followed by phase 2 for activity with the assumption
that short-term effects on cancer, i.e. response rate. It will ultimately lead, if positive, to survival benefits,
including overall survival and progression-free survival. Although this paradigm has been useful in
developing chemotherapeutic drugs, there is much to suggest that we should now broaden our concept
of developmental therapeutics to include the idea of cancer control, as cancer biotherapy becomes more
utilized. As analogue to the treatment of chronic diseases such as diabetes mellitus, it is likely that through
the use of biotherapeutic agents, we may achieve a long-term control of cancer growth and dissemination
without eradication of cancer, i.e. to live with tumor [47,48] . This is often associated with the induction of long-
term memory T cells and/or tumor dormancy. The combined use of DC vaccines, inhibitors (chimeric/
humanized mAbs) of immune checkpoint molecules, such as CTLA-4, or PD1 and chemotherapy on cancer
patients, resulted in survival benefits [1,43,44] .

CONCLUSIONS
The individualization/personalization of cancer treatment represents the major challenge of the next
decade [20,30,45,46] . Clearly, cancer can be characterized on an individual basis and therapy developed for
individual patients. However, bringing this individualized approach to the clinic and merging it with a
more general approach of cancer treatment is a major challenge. One strategy would be to reduce the bulk
of cancer through a more generalized approach, such as surgery, radiotherapy, chemotherapy or targeted
therapy, with application of more specific approach to eradicate or control residual cancer using some form
of biotherapy. Included are manipulation of tumor microenvironment, targeting cancer stem cells, to enhance
T cells infiltration and access to the tumor, augmentation of MHC expression for adequate presentation
of tumor peptide antigens, generated by the treatments. These strategic approaches, while conceptually
pleasing, are difficult to bring into the clinic for individual patients, because of the labor intensiveness, cost
and complicated nature of a multidimensional therapeutic program.

An additional feature is that many of the more specific approaches to cancer treatment, notably, engineered
TCR-T and CAR-T cell therapies [49,50] , and most recently personalized neoantigen peptide or RNA mutanome
vaccines [45,46] are patient-specific and developed in good tissue practice (GTP) or good manufacturing
practice (GMP) laboratories that are remote from clinical trial site. These logistical issues alongside the
governmental regulatory issue are complicated and costly. With the initial success for CD19/CD20-positive
leukemia/lymphoma with CAR-T cell therapy and for melaonoma with neoantigen vaccines, biotech/
biopharma companies and university hospitals/medical centers have both put their great efforts as one
of the top priorities in attempts to bring this type of novel approach to the clinic for other hematological
malignancies as well as many other types of solid tumors [20,37,49-52] .

The major advantages of most cancer biotherapy including cell-based immunotherapeutic strategies are low
or acceptable toxicity, and the ability to target defined molecules, signaling pathways, or cell subpopulations.
On the other hand, biotherapy is more effective in some type of cancers and often needs to be companied by
conventional strategies such as surgery/chemotherapy. Furthermore, good equipped laboratories including
a wet research lab and a government-certified GTP/GMP facility, and at the same time close collaborations