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Oiseth et al. Cancer immunotherapy

ANTIBODIES TO IMMUNE CHECKPOINT study when a cytokine storm was provoked, associated
MOLECULES with multiorgan failure and resuscitation in the intensive
care unit [81] . Since this reaction occurred after the very
In 1996, Leach, Krummel and Allison reported that first infusion of a dose 500 times smaller than that found
safe in animal studies, this study raised awareness of
CTLA-4-blocking monoclonal antibodies (Mabs) the need to develop better animal models which more
could treat tumors in animal models . These MAbs closely mimic drug behavior in humans. In addition,
[72]
became known as “immune checkpoint inhibitors” there was increased appreciation of the wisdom of
(ICIs), although they should really be called “anti- restricting the initial testing of a new pharmaceutical to
immune checkpoint inhibitors” if traditional usage only a few human subjects [82] .
in nomenclature could be easily changed. They are
receiving much attention recently because they are The less toxic antibodies to checkpoint inhibitors have
much less toxic than conventional cancer therapies, shown a great deal of promise and are now approved
are easier to prepare and administer than other types of by the FDA for six malignancies which are in advanced
cancer immunotherapeutics, and have great potential for stages - melanoma, lung cancer, renal cell carcinoma,
widespread application. head and neck cancer, urothelial cancer, and Hodgkin’s

lymphoma - with many other tumor types being
MAbs that have been approved for clinical use target investigated in clinical trials [83,84] . Some of these trials are
either PD-1, PD-L1, or CTLA-4, which “block the negative using specific antibodies to modulate the function of the
blocking” of the T-cells, with a consequent boost of more recently discovered inhibitory and co-stimulatory
the immune response against cancer cells. Assays of checkpoint molecules.
PD-L1 protein expression by immunohistochemistry
are used to determine which tumors would best The immunotherapy/immuno-oncology field has shown
be treated with an anti-PD-L1 antibody, but it is an such exponential gains in recent times, associated with
imperfect measurement practice because there is lack an accumulation of a dizzying array of complex results
of standardization of methods and it can sometimes arriving from numerous clinical trials, that mechanistic
be difficult to differentiate PD-L1-positive tumor cells patient studies are necessary to best advance
from the other PD-L1-positive cells in the tumor understanding. This is essentially “reverse translational
microenvironment [73] . Moreover, immunohistochemistry research”, or the opposite of the usual “bench to
has a lower sensitivity compared to studies measuring bedside” philosophy, requiring genetic, phenotypic,
PD-L1 mRNA expression [74] . functional, and immunohistochemical studies of pre-
treatment, on-treatment, and post-treatment tissues.
Anti-PD-1 and anti-PD-L1 antibody treatments are These are necessary in order to generate hypotheses
currently the most investigated ICIs because they have that can then be tested in animal models and thereby
shown less severe toxicity, or high-grade “immune- provide more precise biologic pathways about tumor
related adverse effects” (irAEs), than anti-CTLA-4 immunity and rejection [85] .
antibody treatments (5-20% compared to 10-40%
respectively) [75-79] . The wide ranges in the percentages Some of the complexities of interacting with the immune
of adverse effects reported reflect the variabilities system include timing of administration of ICIs to coincide
associated with single or multiple drug regimens, with a high inflammatory microenvironment in the tumor
dosage levels, and types of malignancies treated. The to ensure the presence of many potential tumor-fighting
more common side effects are fatigue (with or without CD8 T-cells [86,87] . This often correlates with tumor
+
associated endocrinopathies), dermatologic and necrosis provoked by prior conventional chemotherapy,
mucosal toxicities, diarrhea/colitis, and hepatotoxity. and is also related to the number of mutations present
Corticosteroids or other immunomodulators can reverse in the tumor (“mutational burden”), which is associated
nearly all of the toxic manifestations of these drugs [75-78] . with higher antigenicity and correlates positively with
Pneumonitis is an uncommon but potentially severe response to ICIs . Lung cancers occurring in smokers
[88]
complication, and rarely deaths have occurred [80] . As have a higher mutational burden and have shown more
the authors noted in one comprehensive review article responsiveness to ICIs . Microsatellite instability-high
[89]
about management of immunotherapy toxicities, “This colorectal cancers, which tend to have a high-mutation/
new family of dysimmune toxicities remains largely high-neoantigen load based on owing their genesis to
unknown to the broad oncology community [77] ”. a deficiency in DNA repair, have also been proven to
respond well to ICIs [90,91] . Even the patient’s intestinal
These drugs have powerful effects, as seen when a bacteria needs to be considered, as noted in two
Phase I trial using an antibody to the CD28 ligand nearly recent reports: in one study of patients with metastatic
cost the lives of all six healthy volunteers in a British melanoma treated with anti-PD-1 antibody, the diversity
256 Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ October 31, 2017