1. 92 | Pharmaceutical Engineering | March-April 2016
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Recent advances in drug development reflect
this by alluding to the concept of a magic bullet.
The term was coined in the early 1900s by Paul
Ehrlich, a German hematologist and immunolo-
gist, who sought the means to deliver a deadly
payload specifically to cancer cells. Having used
methylene blue as a therapeutic agent against
the malaria pathogen, he imagined the possibil-
ity of precise delivery of such a toxin – or magic
bullet – by virtue of its being coupled to a com-
pound that targeted the disease-causing organ-
ism. What was needed was a toxin, a delivery
system and a way to link the two. The concept
was extended to cancer therapy but it would take
a century to arrive.
The first chemotherapy treatments were aimed at
one of the chief characteristics of cancerous cells;
they have escaped from the normal inhibitors
that prevent the division of mature cells. The
compounds that were chosen damaged DNA
or prevented cellular division by other means.
Among these were alkylating agents, such as
nitrogen mustards, which bind covalently to
DNA, RNA and proteins, rendering them inactive;
antimetabolites, such as methotrexate, which
interferewithcellularmetabolism,oftentargeting
DNA synthesis; and anti-microtubule agents
that interfere with cell division by disrupting
normal microtubule assembly or disassembly,
thus truncating mitosis. The damage either
prevented DNA replication and division outright
or instigated cell cycle arrest and programmed
cell death. The problem with these treatments
has always been (to continue the martial
imagery) collateral damage from friendly fire;
cancer cells are not the only cells in our bodies
that divide – hair follicles and the healthy lining
of the gut are among tissues that also succumb
to chemotherapy.
These days
we might allow
ourselves to believe
that Cancer
Can Be Beaten
is not just a hopeful
slogan; it might
actually be true.
Recent exciting developments in oncology that
stimulate or manipulate the immune system to
treat cancer have resulted in protocols that tend
to have fewer side effects, can be used longer and
can be combined with other chemotherapies or
treatmentswithoutaddingtosideeffects.Among
the promising immunotherapies are checkpoint
inhibitors, which work by blocking molecules that
inhibit immune response or activating stimulato-
ry molecules. The FDA has approved seven such
therapies for melanoma in the past five years,
including the monoclonal antibody checkpoint
inhibitors Yervoy (ipilimumab), which targets
CTLA-4, and the two anti-PD-1 agents Keytruda
(pembrolizumab) and Opdivo (nivolumab).1, 2, 3, 6
Other promising immuno-oncology treatments
include adoptive T cell therapy (CAR-T) – in
which a patient’s T cells are removed, genetically
modified to recognize antigens that are unique to
that patient’s cancer cells and reintroduced into
the patient4
– monoclonal antibodies, therapeu-
tic vaccines, oncolytic viruses and cytokines.
But perhaps the targeted treatment most like
Ehrlich’s magic bullet are antibody drug conju-
gates (ADCs). ADCs have three components: an
antibody,apharmaceuticallytoxicpayload,which
is usually a microtubule inhibitor, and a chemical
linker.5
While many ADCs are in development,
one area they are currently being used is in breast
cancer, where treatment usually requires surgery
followed by chemotherapy, radiation therapy,
hormone therapy or targeted therapy.6
Targeted
therapies for cancers that overexpress the HER2
receptor include trastuzumab (Herceptin), pertu-
zumab (Perjeta), lapatinib (Tykerb) and ado-tras-
tuzumab emtansine (Kadcyla).6
We have basic science advances in molecular
biology, immunology and cell biology to thank
for this current spate of breakthrough biologics.
These days, among the pink ribbons, PSAs and
people willing to be vocal about their colonos-
copies, we might allow ourselves to believe that
Cancer Can Be Beaten is not just a hopeful slogan;
it might actually be true. ¢
Scott Fotheringham, PhD and James Hale
In ancient Greece, doctors such as Hippocrates and Galen considered
cancer – which Hippocrates named – incurable. Since then, the
dominant metaphor we’ve used to describe our relationship to this
formidable foe has been martial: we wage war on cancer, patients
battle the disease and we encourage ourselves that cancer can be
beaten. An obscene, two-word, online meme, often posted when a
well-known person succumbs to the disease, expresses the kind of
direct, personal aggression we expect in combat.
References
1. Cancer Research Institute. “Melanoma.” Updated October
2015.www.cancerresearch.org/cancer-immunotherapy/
impacting-all-cancers/melanoma
2. Palmer, E. “Bristol-Myers Leads Immuno-oncology Race
but Merck, AstraZeneca and Roche Still Have Contenders.”
FiercePharma. 26 February 2016. www.fiercepharma.com/
story/bristol-myers-leads-immuno-oncology-race-merck-
astrazeneca-and-roche-still/2016-02-26
3. Bristol-Myers Squibb Canada Co. “Health Canada approves
OPDIVO™ (nivolumab) for the treatment of advanced or
metastatic non-small cell lung cancer.” Newswire. www.
newswire.ca/news-releases/health-canada-approves-
opdivo-nivolumab-for-the-treatment-of-advanced-or-
metastatic-non-small-cell-lung-cancer-570647091.html
4. Juno Therapeutics. “T Cell Receptor Technology.” https://
junotherapeutics.com/our-science/tcr-technology/
5. Marshall, P.J. et al. “Issue with the Safe Handling of Antibody
Drug Conjugates.” Pharmaceutical Engineering 35, no.3
(May/June 2015): 90-103.
6. Cancer Research Institute. “Breast Cancer.” UPdated
September 2014. www.cancerresearch.org/cancer-
immunotherapy/impacting-all-cancers/breast-cancer
Quest for the Magic Bullet