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The Era of Immunotherapeutics: Overcoming
the challenges to fulfill the potential
SUMMARY
Immunotherapeutics are changing the paradigm in cancer treatment by stimulating
the patient’s immune system. However, unique challenges still prevent widespread
adoption of these agents and must be overcome if we are to realize their full potential.
Although a great amount of information is known and more understanding is gained
every day, technologies that will help unravel these complexities and support the
development of safe and effective therapies are still needed.
Breakthroughs in the field of immunotherapeutics
are changing the way we treat many cancers.
Immunotherapeutics are changing the
paradigm in cancer treatment and hold
great promise for use in other disease
areas as well. These agents bring about
their therapeutic effects by stimulating
the patient’s immune system. The
quest to identify and develop new
immunotherapeutics has become one
of the most active areas in cancer
research, bringing the exciting possibility
of robust and long-lasting treatment
response in patients with fewer side
effects than traditional chemotherapies.
However, unique challenges still prevent
widespread adoption of these agents and
must be overcome if we are to realize
their full potential. Solving these issues
requires us to better understand the
complex pathways involved in disease
progression and immune response along
with the intricate interactions between
the two. Although we already know
a great amount and are learning more
every day, we need tools that will help
us unravel these complexities and
support the development of safe
and effective therapies.
Figure 1. Some notable events in the
development of immuno-oncology therapies.
While the main focus
of immunotherapeutics so far has
been in oncology, they could be
used in autoimmune, infectious, and
neurodegenerative diseases as well.
The underlying biology differs across
diseases, but the ways to modulate
the immune system are similar,
so technologies developed for the cancer
area will likely be applicable to other areas.
(1) Once we learn how to reliably and
safely apply these treatments, the benefit
to risk profiles will be more suitable for
increasing application in other diseases.
Unique challenges associated
with immunotherapeutics
Target and candidate selection
Discovery and development of
immunotherapeutics differs from that
of traditional small molecule drugs. While
novel small molecule candidates can be
discovered using high-throughput screens
without prior knowledge of the molecule’s
target, immunotherapies require a great
deal of knowledge, as they are specifically
designed based on the target, its role in
the disease pathway, and the interactions
between the immune system and the
disease. Immunotherapeutic agents
are also very diverse, including
antibodies, cells, cytokines, viruses,
and other biologics.
As our knowledge of the immune
system and disease pathways increases,
so does the number of potential
immunotherapeutic targets. We are still
learning how cancer cells avoid detection
and attack by our immune systems. These
evasion pathways offer many attractive
targets for designing therapeutics.
However, disease and immune pathways
are already complex individually.
Considering each in the context of the
others compounds the challenge
of fully understanding all of the important
interactions. To succeed, we must be
able to see exactly how each piece of
information fits into the overall picture.
Models and biomarkers
A lack of suitable assays and models
complicates mechanism of action
studies for potential immunotherapeutic
candidates. Our inability to accurately
predict toxicity and treatment outcomes
hinders development of these therapies.
Furthermore, due to disease and patient
heterogeneity, not all people will profit
from a particular immunotherapeutic,
so biomarkers that can identify those
patients most likely to benefit must
be developed.
2
Adverse events
Unwanted irAEs pose a serious challenge
to the immunotherapeutics field.
Exaggeration of on-target interactions can
lead to infections, malignancies, cytokine
release syndrome (CRS), tumor lysis
syndrome, and autoimmunity.(2) Intrinsic
properties of an immunotherapeutic such
as immunogenicity can cause production
of anti-drug neutralizing antibodies or
lead to hypersensitivity reactions.(2) Plus,
unanticipated interactions with healthy
cells can lead to toxicities and other
off-target effects.
Systematic characterization of irAEs
in recent years has made it possible
to include mitigation strategies in clinical
treatment algorithms.(3) However,
complete risk management requires that
we understand the complex interactions
among the disease, the immune system,
the target, and the immunotherapeutic
candidate. Reliable prediction of irAEs
is critical to managing them quickly and
effectively without patient harm, but
there is still a lack of tools to predict their
likelihood and severity.
Development
Immunotherapeutics such as the
anti-CTLA4 antibody ipilimumab initially
followed the traditional approach
to oncology chemotherapy drug
development, but it became clear in the
process that a new development paradigm
was needed.(4) Conventional endpoints
were not suitable for assessing the
efficacy of immunotherapeutics, so new
immune-related response criteria were
defined with endpoints more appropriate
for these agents. In addition, strategies
for mitigating irAEs were included in the
treatment protocols.(4)
Manufacturing and logistics
Autologous cellular therapies are
associated with several special logistical
issues related to production and
administration. Harvesting a patient’s
cells usually takes place in one facility,
while the subsequent ex vivo cell
treatments occur in another. Maintaining
chain of identity across various sites and
ensuring quality control throughout the
entire process are difficult challenges that
cannot be compromised.
Combining multiple therapies
Although immunotherapeutics are
demonstrating much success, many
cancer patients do not respond to
treatment with just a single agent.
Combining multiple therapies into
a treatment regimen can potentially
increase the number of patients who
will benefit by decreasing toxicity profiles,
overcoming resistance issues, and
improving the level and duration
of response.
Many trials are underway
assessing various combinations
of immunotherapeutics or
immunotherapeutics combined with
radiation or chemotherapy. Optimizing
these complex treatment regimens poses
a significant challenge. It is difficult
to predict how combining multiple
therapies will affect treatment responses
and toxicity issues. Determining the
optimal dose for each therapy, how often
to administer the therapies, the treatment
sequence, and treatment durations are
other issues that complicate optimization
of multi-therapy combinations.(5)
The evolving landscape
of immunotherapeutics
Imunotherapeutics can be classified into
two broad categories: passive and active.
Passive immunotherapeutics include
various immune components such as
antibodies and T cells that are designed
to directly target and kill tumors. Active
immunotherapeutics, on the other hand,
are designed to harness the power of
the host immune system to kill the
tumors for us. As we learn more about
the interactions between cancer and the
immune system, our ability to design
more advanced therapies against more
complex targets will continue to evolve.
The immune system can detect
and suppress early tumor growth
to prevent cancer, but despite this
immunosurveillance, tumor cells still
frequently evade detection and develop
into cancer, becoming less immunogenic
in the process.(6) Widespread research
is underway attempting to tweak the
immune system so it will once again
recognize these cancer cells as foreign
and attack them.
3

Resistance to Monoclonal
therapy is difficult
to understand, because
the multiple mechanisms
by which mAbs can
elicit anti-tumor effects
translate into multiple
ways by which resistance
can develop, which
is a major challenge.
Anticancer monoclonal
antibodies (mAbs)
The introduction of anticancer mAbs
revolutionized cancer treatment
approaches, shifting the paradigm from
use of general anticancer treatments
to molecularly targeted agents designed
to kill specific tumors. Anticancer mAbs
locate and attach to tumor-specific
antigen targets and then kill the tumor
cells or prevent their proliferation via
various mechanisms.(7) Some antibody
isotypes bind to complement proteins
and induce a cytolytic cascade that
kills the tumor cells via complementdependent cytotoxicity (CDC). Other
mAbs bind to various immune effector
cells, enabling the effectors to attack and
lyse the antibody-coated tumor cells via
antibody-dependent cellular cytotoxicity
(ADCC). Yet another mechanism is for the
anticancer mAbs to bind tumor-specific
cellular receptors or circulating proteins,
blocking the pathways essential for tumor
cell growth.
Identifying optimal targets for designing
anticancer mAbs is still difficult. A good
target must be expressed at high levels
exclusively on tumor cells to prevent offtarget toxicity to healthy cells. Targeting a
pathway critical to tumor growth requires
comprehensive knowledge of both how
the pathway operates in the context of the
disease and how blocking it may affect
other functions important to our health.
While our knowledge of pathways and
their interactions is large and still growing
rapidly, actually understanding how all the
pieces fit together into the big picture
is no small feat.
One well-studied anticancer mAb target is
human epidermal growth factor receptor
2 (HER2), which is overexpressed in
around 20-30% of breast cancers and has
been associated with aggressive disease
and poor prognosis.(8) HER2 normally
promotes cell growth and division, but
increased amounts of the receptor on
tumor cells activate other pathways,
including MAPK, PI3K/AKT, and NF-κB.
(8) The result is a constant signal for the
tumor cells to proliferate. Trastuzumab
(Herceptin) is a mAb designed to treat
HER2-positive breast cancers, and it
functions by binding HER2 and blocking
its ability to send these signals.
In addition to the desired therapeutic
activity, the on-target effects of various
anticancer mAbs have also been
associated with the incidence of irAEs,
including increased risk of infections,
development of progressive multifocal
leukoenephalopathy (PML), and cytokine
release syndrome (CRS).(2) Trastuzumab
is no exception, and binding to its target
downregulates neuregulin-1 (NRG-1),
increasing the chance of developing
serious heart problems.(9) It turns out
that the same pathways involved with
progression of these cancers are also
critical for normal cardiac function. Thus,
it is important to balance the therapeutic
benefit of an agent against its ability
to cause adverse events. To assess this
effectively, we must fully understand the
involved pathways in detail and their roles
in both disease and healthy states.
The first anticancer mAbs were of murine
origin, and patients recognized the agents
as foreign, mounting immune responses
against them, but we have since overcome
this problem by using human, humanized,
or chimeric antibodies instead.(7) One
issue that still needs work is developing
appropriate biomarkers to predict which
patients will likely respond to treatment.
Trastuzumab was developed using a
biomarker-enrichment design strategy,
in which only patients with HER2-positive
tumors were enrolled in the trials,
increasing the likelihood of a successful
therapeutic effect.(10) This was possible
due to an abundance of data showing the
importance of HER2 in the disease and
the strong antitumor response resulting
from blocking it.However, these details
are not always so clear for all candidates
and targets, and including the wrong
patients in trials can result in lack
of efficacy or even patient harm.
Patients who do not respond to treatment
with anticancer mAbs can rapidly
develop resistance, which is a major
problem facing the field.(11) Resistance
is difficult to understand, because the
multiple mechanisms by which mAbs
can elicit antitumor effects translate into
multiple mechanisms by which resistance
can develop. In addition, using mAbs
in combination with other therapies
further complicates attempts to unravel
resistance mechanisms. Existing murine
4
Anti-tumor antibodies
(HER2/neu, CD20)
Immune checkpoint inhibitors
(CTLA-4, PD-1/PDL-1)
Adoptive cell transfer
(CAR T cells, DCs)
Provoking
anti-cancer
immune
response
Co-stimulatory agonists
(4-1BB)
Vaccines
(peptides, viruses)
Antibody-drug conjugates
(CD30, HER2/neu)
Oncolytic viruses
(HSV1716, H101)
Angiogenesis blockers
(VEGF)
Figure 2. Central to all immune therapies
is boosting the anti-cancer response using
the patient’s own immune system. This
illustration identifies the main categories
of immunotherapeutics based on their
mechanisms. Each therapeutic has unique
benefits and challenges.
models are poorly suited for analyzing
resistance to ADCC and CDC antitumor
effects due to the differences between
our immune systems and theirs, so we
still have a lot to learn in this area.
Anticancer mAbs have been very
successful therapeutic agents and are
widely used against various types
of cancer, usually in combination with
another treatment. Although new types
of immunotherapies are coming into
focus, anticancer mAbs are still very
useful. Efforts to identify and validate
new targets and engineer antibodies with
improved antitumor response will help
keep the area active for some time.
Immune checkpoint inhibitors (ICIs)
ICIs are a new class of immunotherapeutic
that is changing the cancer treatment
paradigm once again. Instead of targeting
the tumor directly, ICIs target the patient’s
immune system and restore the natural
anti-tumor immune response. Since the
approval of ipilimumab in 2011 for treating
advanced melanoma, the interest in these
agents has grown rapidly, intensifying
efforts to identify novel immune
checkpoint pathways and targets.
Selecting a target for an ICI requires
a thorough understanding of how
immune checkpoints work and how
blocking them will affect the disease
and our health. Immune checkpoints are
co-inhibitory or co-stimulatory molecules
that prevent attacks on healthy cells, but
they can also keep our immune systems
from attacking cancer cells. ICIs target
these molecules and allow the immune
system to remain activated.
The two best-characterized immune
checkpoints are CTLA-4 and PD-1/PDL1. CTLA-4 is a surface T-cell receptor
that inhibits the co-stimulatory signal,
thereby preventing subsequent activation
of antitumor T-cell responses.(3) The
regulatory role of PD-1 comes after T-cell
activation. Binding of PD-1 to PDL-1
(programmed death ligand 1) suppresses
migration and proliferation of T-cells,
restricting killing of cancer cells.(3)
Blocking these immune checkpoints
therapeutically activates the immune
system and restores the antitumor
immune response. To date, there are
three approved immune checkpoint
inhibitors, all of which are mAbs.
Ipilimumab targets CTLA-4 and was
5
Immunotherapy
Research
1. Expanding data
Knowledge on cancer and
immune signaling pathways
continues to grow rapidly.
2. Fueling innovation
Unraveling the complexities of
the interactions between disease
and immune pathways will lead
to the development of new
predictive models.
3.Developing the
right medicine for
the right patients
Many different types of immune
therapies exist today with many
more in development pipelines,
providing a ever growing arsenal
to help fit the right medicine
with the right patient.
the first checkpoint inhibitor approved
for treating advanced melanoma.(12)
Nivolumab and pembrolizumab have
been approved for treatment of previously
treated metastatic non-small-cell lung
carcinoma (NSCLC).(12) Both function
by blocking PD-1:PD-L1 binding, allowing
T cell proliferation and production of
inflammatory cytokines at the tumor site.
While ICIs restore antitumor responses,
the nonspecific stimulation of T cells they
induce is associated with various unique
irAEs, which usually involve problems
with the skin, liver, and gastrointestinal
or endocrine systems.(12) Most patients
receiving ICI treatment experience irAEs,
which can range from mild to severe
or occur at any time from soon after
treatment up to many months later.
These are often manageable with highdose corticosteroids or other immune
suppressants. However, about 10%
of patients experience life-threatening
irAEs that require hospitalization.(13) We
have no biomarkers to predict which
patients will be affected or how severely,
but improving our understanding of
immune pathways and how an individual’s
immune status affects response will
certainly aid in their development.
Development of ICIs must take into
account the differential response
of tumors to this class of agents. In some
patients the tumor volume or number
of lesions appears to increase initially
upon treatment initiation.(14) This
appearance of disease progression
is often caused by immune activation and
infiltration of the tumor by inflammatory
T cells. Furthermore, in some patients the
time for a complete response can be very
long, up to 30 months for ipilimumab,
for example.(15)
As with other immunotherapeutics,
ICIs are not effective in all patients,
so we need to development predictive
biomarkers for efficacy and toxicity.
Efforts to identify and validate such
biomarkers are underway, but since these
agents target the immune system instead
of the tumor, the patient response is
more complicated and involved a variety
of parameters, including serum protein
markers and immune cell phenotypes
and functions.(16) Determining the roles
of these different parameters in efficacy
and toxicity is difficult and requires that
we understand a number of complex
pathways in the context of each another
Other types of immunotherapeutics
Many other types of immunotherapeutic
agents and strategies are already in use
or in various stages of development. Tools
that can help us better understand the
diseases and immune pathways involved
will support their success in the clinic.
Adoptive transfer of T cells expressing
chimeric antigen receptors (CAR) has
shown remarkable efficacy in clinical
trials, bringing hope to certain patients
with no further treatment options.(17)
Co-stimulatory agonists targeting T
cells are able to initiate several different
signaling cascades and strengthen
antitumor T cell receptor signaling.(18)
Efforts to create peptide-based vaccines
to force the immune system to attack
cancer cells have led to many failures, but
better selection of targets and vaccine
format may change that in the future.
(19) Antibody-drug conjugates (ADCs)
comprising a monoclonal antibody, a
linker, and a payload can selectively
deliver highly toxic payloads to specific
disease sites. Oncolytic viruses that
replicate in tumor cells release antigenic
proteins that initiate a T cell response
against the tumor cells. The tumor
microenvironment (TME) also contains a
number of potential targets involved in
tumor growth and dissemination and is
an area of great interest.(20)
Looking to the future
Breakthroughs in the field of
immunotherapeutics are changing the
way we treat many cancers and bring the
promise of durable, long-term survival
to many patients. While our knowledge
regarding various cancer pathways and
immune signaling pathways has grown
immensely and continues to grow,
we must develop a comprehensive
understanding of how disease pathways
interact with immune pathways.
Unraveling the complexities of these
important interactions and combining this
knowledge with new predictive models
will help translate preclinical promise into
clinical success for treating cancers and
other diseases.
6
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