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Oiseth et al. Cancer immunotherapy

and composition of the gut microbiome differed in The pharmacoeconomics of these treatments also
responders versus non-responders, with the non- needs to be considered. The cost of the typical treatment
responders showing less diversity and higher abundance using antibodies to ICIs is near $150,000 a year. A
of Bacteroidales, while the responders had higher combination of ipilimumab and nivolumab, approved by
diversity and a higher abundance of Clostridiales . the FDA for advanced or inoperable melanoma, has a
[92]
Another study of patients with metastatic renal cell cost of $256,000 a year for patients who respond to
carcinoma showed faster tumor progression in the the treatment [97] . Some relief may be obtained by the
patients who had received broad-spectrum antibiotics entry of at least some less costly biosimilars, which
up to one month before treatment with ICIs . are biological products that must be “highly similar” to
[93]
the original reference product, per FDA regulations.
Not all immune checkpoint or immunomodulatory Biosimilars are usually made by a different/competing
molecules take the form of a receptor or ligand. Some company [98] .
may be expressed by the cell in a free soluble form,
such as indoleamine 2,3-dioxygenase (IDO1), an Immunotherapy drugs are now approved for treatment
enzyme produced by some activated macrophages and of multiple cancer types either as first-line treatment
also overexpressed by many tumors [94] . The enzyme or when standard first-line treatment has failed. The
depletes tryptophan in the microenvironment, with FDA has recently approved the anti-PD-1 antibody
production of the catabolite kynurenine, which harms pembrolizumab for the treatment of any unresectable
the cytotoxic T-cells. Phase I/IIa studies of one IDO1 or microsatellite instability-high or mismatch repair-
inhibitor show promise [95] . deficient solid tumors that have progressed after prior
treatment and who have no other satisfactory treatment
options [99] . This is the first time the agency has approved
CONCLUSION a cancer treatment based on a common biomarker
rather than the location of the body where the tumor
With the development of the field of cancer originated.
immunotherapy, the focus of treatment has shifted from
treating the disease site to treating the specific tumor Immunotherapies do not yet represent a panacea
biologic characteristics and its interaction with the intrinsic in cancer therapy since only a minor subset of some
immunological ability or “cancer immune set-point” of the cancers respond to some of these treatments, and it is
patient to combat the disease. Since the immune system difficult or impossible to determine precisely who will
has the capacity to remember and the ability to detect and benefit.
destroy tumor variants as they emerge, immunotherapy
will always possess inherent advantages over other Before finishing this brief review, it is proper to recognize
therapies that lack these two key attributes. The the work of Dr. James Allison of Houston’s MD Anderson
challenges ahead are to discover why immunotherapy Cancer Center in Texas, the winner of the 2015 Lasker
treatments work so dramatically well in some cancers Award, since he is the one who discovered the T-cell
receptor in 1982 and went on to develop the field of
and in some patients while not at all in others, and how checkpoint blockage, leading to the breakthrough drug
tumors which were once sensitive to treatment can ipilimumab [100,101] .
acquire resistance. Specifically, to be effective, cancer
immunotherapy needs to find ways to manipulate the DECLARATIONS
immune system in the (probable majority of) patients
who show little or no immune response to their tumors, Authors’ contributions
even to the point where the tumor microenvironment is Both authors contributed equally to this review.
an “immune desert” with no tumor-infiltrating T-cells [86,87] .
Breakthrough discoveries will be necessary to be able Financial support and sponsorship
to consistently elevate a patient’s cancer immune set None.
point and to recover MHC class I antigens in those
tumors that downregulate them. One recent study with Conflicts of interest
large therapeutic and prognostic implications used the There are no conflicts of interest.
new CRISPR technique to reveal multiple mutations
in the tumor genes of individual patients who failed Patient consent
immunotherapy . Some of these identified genes may Not applicable.
[96]
be associated with loss of tumor antigen expression,
while others may involve disturbances in tumor cytokine Ethics approval
production or T-cell co-stimulation. Not applicable.
Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ October 31, 2017 257