The R&D Tax Credit Aspects of Immunology
Immunology
For over three centuries, immunological research has
lead to major health advances. From the development of modern vaccines
to safe organ transplantation, the identification of blood types and
the use of monoclonal antibodies, immunological innovation has
revolutionized healthcare and saved countless lives. Nowadays,
immunology continues to be one of the most important branches of
medical research, including critical areas such as immunotherapy,
autoimmune and immunodeficiency diseases as well as the development of
new vaccines for emerging threats. The present article will give an
overview of recent advancements and outstanding challenges in
immunological research. It will also discuss how R&D tax credits
can support companies engaged in expanding our understanding of the
immune system as well as developing new clinical and commercial
applications for immunology-related findings.
The Research &
Development Tax Credit
Enacted in 1981, the federal Research and
Development (R&D) Tax Credit allows a credit of up to 13% of
eligible spending for new and improved products and processes.
Qualified research must meet the following four criteria:
- New or improved
products, processes, or software
- Technological in nature
- Elimination of
uncertainty
- Process of
experimentation
Eligible costs include employee wages, cost of
supplies, cost of testing, contract research expenses, and costs
associated with developing a patent. On December 18, 2015,
President Obama signed the bill making the R&D Tax Credit
permanent. Beginning in 2016, the R&D credit can be used to offset
Alternative Minimum tax and startup businesses can utilize the credit
against $250,000 per year in payroll taxes.
The Immune System
The immune system is absolutely essential for human
survival and wellbeing. It provides various lines of defense against
infections, suppresses the growth of tumors, and initiates the repair
of damaged tissues. Equipped with an army of B and T lymphocytes, the
immune system is able to recognize different molecular patterns present
in pathogens or expressed by injured or infected host cells. By
differentiating such patterns from the ones present in healthy cells
and tissues, the immune system provides biochemical and cellular first
responders against various threats.
The study of anatomy functions and malfunctions of
the immune system is a highly promising way to advance the
understanding of human health and disease, including many conditions
that are not traditionally viewed as immunologic, such as metabolic,
cardiovascular, neurodegenerative, and neoplastic diseases.
Made up of a complex combination of processes and
structures, the immune system consists of molecular and cellular
components that specialize in either innate or adaptive immunity.
Nonspecific, innate mechanisms work as the first line of defense,
offering the same kind of response to all potential threats. Innate
immunological barriers are both physical, such as the skin and saliva,
and cellular, which include macrophages, neutrophils, basophils, mast
cells, etc.
When the first line of defense is not enough, the
body resorts to adaptive immune functions, mainly through the action of
antibodies and T-cells. Adaptive immunity allows for the creation of a
memory of previously encountered infections that enable specific
responses to pathogens and foreign substances to which the host has
already been exposed.
Understanding the complexities of the immune system
remains a substantial challenge. There are major ongoing efforts to
comprehend the genomic, epigenomic, transcriptional, and functional
features mediating adaptive immunity as well as the many different
subsets and functional states of the immune cells. Researchers at the
Bar Harbor, Maine-based Jackson Laboratory (JAX) in collaboration with
French Institut Curie have recently unveiled a key mechanism that can
significantly contribute to immunology research advances. They
demonstrated how dendritic cells (DCs) do their job while avoiding
getting infected. DCs are crucial to promoting adaptive immunity, as
they round up viral antigens and present them to T-cells, which then
trigger immune responses. The research concluded that two subsets of
DCs work together for antiviral response. One of them dies and produces
the viral antigens, while the others take these proteins to the
T-cells. This finding can help advance the goal of using DCs as the
basis for new treatment options.
In vivo confocal and multiphoton imaging of
pathogen-host cell interactions are also an important area of research
for advancing the understanding of immune mechanisms. Headquartered in
Ann Arbor, Michigan, Essen Bioscience is the creator of IncuCyte, an
innovative live-cell analysis system that is contained within an
incubator and thus enables the monitoring of cells over time. By
providing information-rich analysis of biological processes, it can be
used to support the investigation of lymphocyte activation, autoimmune
reactions, and vaccine response.
A better understanding of immunological functions
can revolutionize various areas of healthcare, organ transplantation
being one of them. Following a transplant, the immune system may
consider the new organ as foreign, causing serious complications.
Immunosuppressive drugs have played a crucial role in preventing organ
rejection, however they also put patients at higher risks of infection.
Researchers at the University of Virginia School of Medicine have
recently received over $8.6 million in federal grants to increase the
rate of successful lung transplant. Their efforts include creating a
mechanism to induce tolerance to lung drafts. They are experimenting
with cells and antibodies that can potentially kill harmful T-cells
without the need for immunosuppression therapy.
French biotechnology company TxCell has recently
appointed Gaithersburg, Maryland-based Lentingen Technology to
manufacture a lentiviral vector that will serve as the basis of a new
product candidate for the prevention of transplant rejection. TxCell’s
goal is to tackle one of the main causes of transplant rejection:
incompatibility between the donor’s and the recipient’s human leukocyte
antigen (HLA) systems. The vectors will be used to engineer regulatory
T-cells (Tregs) with a Chimeric Antigen Receptor (CAR), which is
specific for HLA-A2, one of the forms of the HLA histocompatibility
system. HLAA2 CAR-Treg cells will be designed to specifically recognize
an HLA-A2+ graft and trigger a reduction of inflammation as well as an
induction of immune tolerance in a local and specific manner thus
reducing graft rejection.
Immunological Dysfunctions
and Diseases
There are several conditions that are related to
defects in the immune system or that arise when immune responses damage
host cells and tissues instead of targeting foreign molecules.
Together, immunodeficiency and autoimmune diseases cause significant
morbidity and mortality worldwide. While immunodeficiency diseases are
caused by gene mutations, malnutrition as well as certain viruses and
medications, autoimmune conditions are related to a combination of
inherited genes and environmental factors.
One in every fifteen Americans suffers from
autoimmune diseases, which are among the ten greatest causes of death
in women and cost the nation over $100 billion a year in medical care.
An important example is lupus, a chronic inflammatory disease in which
the immune system attacks host tissues and organs. Capable of affecting
multiple body systems - including joints, skin, kidneys, and lungs –
lupus is often hard to diagnose as its symptoms are similar to those of
other ailments. Even though there is no known cure for lupus, the
identification of biological pathways to be targeted promises to open
the way for new, personalized treatments.
A recently published study by an international
consortium led by researchers at Wake Forest Baptist Medical Center,
Oklahoma Medical Research Foundation, King's College of London, and
biotech company Genentech Inc. has identified a large number of new
genetic markers that predispose individuals to lupus. The study focused
on the patterns of incidence of the disease, which is nine times more
prevalent in women than men, particularly in African-American and
Hispanic populations. The multi-ethnic effort analyzed data from over
27 thousand individuals. The results shed light on the genetic
differences and similarities that can begin to explain varying rates
and severity of lupus across ethnic groups.
Ongoing immunology research also shows great promise
in improving the lives of millions Americans who live with type 1 and
type 2 diabetes. Type 1 diabetes is an autoimmune disease that occurs
when the immune system prevents the body from synthesizing insulin by
mistakenly destroying insulin-producing beta cells in the pancreas.
Most common in children and young adults, this condition can be managed
with insulin therapy or similar treatments that, however successful,
represent a life-long dependency. In type 2 diabetes, the immune
dysfunction takes a different form: there is chronic inflammation that
causes insulin resistance, making the patient unable to use insulin to
transform sugar from food into energy.
Researchers at the Hackensack University Medical
Center in New Jersey are working on a groundbreaking treatment that can
change the lives of diabetes patients. Initially developed in China,
the “stem cell educator therapy” consists in exposing immune system
cells (lymphocytes) from a person with diabetes to stem cells from the
umbilical cord blood of a healthy infant. Surprisingly, after this
exposure, when returned to the body, the previously errant lymphocytes
behave normally and no longer attack beta cells. In the case of type 2
diabetes, there is hope that this treatment will decrease insulin
resistance. Even though results are only preliminary, this innovative
approach shows great promise for a wide variety of autoimmune diseases.
Rheumatoid arthritis (RA) is yet another example of
autoimmune disease. This chronic inflammatory condition occurs when the
immune system attacks the body’s systems, especially the joints,
causing painful swelling that can result in the erosion of bones as
well as joint deformity. There are major research efforts aimed
at preventing the physical disabilities that ensue from RA. Researchers
at Brigham and Women's Hospital in Boston have recently unveiled
evidence that eating fish may reduce inflammation and joint pain in RA
patients. In the study, participants who consumed two or more servings
of baked, steamed, broiled, or raw fish per week had significantly
lower disease activity scores.
The development of effective RA medication remains a
great challenge, particularly due to safety concerns. On August 2,
2016, an advisory panel to the FDA voted against the approval of
Johnson & Johnson’s experimental drug Sirukumab, pointing out that
its benefits did not outweigh its risks. Further R&D efforts are
necessary to prevent concerns related to heart problems, infection, and
malignancies surrounding RA drugs. The FDA panelists further stressed
the need for groundbreaking, innovative therapies rather than new drugs
using the same mechanisms that are already present in similar
medications available on the market.
Other immune system-related diseases are caused by
excessive or chronic responses, such as asthma, as well as
hypersensitivity to non-pathogenic antigens, which can cause allergies.
In allergic reactions, the immune system produces substances to attack
the allergen, which is mistakenly believed to be dangerous. Researchers
at the Seattle-based non-profit organization Benaroya Research
Institute have recently identified the T-cells that indicate when a
person has allergic responses. The Th2A only exists in those who have
allergies and could thus potentially be the basis of a blood test for
newborns or even a novel immunotherapy targeting allergy-inducing
T-cells.
Immunology and Microbiome
Research
The immense community of microbes residing in and on
the human body is collectively known as the microbiome, or
microbiota. Besides bacteria, it includes archaea, viruses, and
eukaryotic organisms that perform crucial tasks, such as contributing
to metabolic functions. The microbial community in the body is key for
the education of the immune system, which must learn to tolerate it
while appropriately responding to pathogens. In fact, microbes play a
crucial role in developing and guiding immune responses. Research has
revealed that changes in our microbiome accompany various health
conditions.
A growing number of studies have pointed to the
possible influence of gut bacteria on immune activity, particularly in
individuals suffering from autoimmune diseases. Researchers at the Mayo
Clinic found that the microbiome of multiple sclerosis (MS) patients is
different from those of healthy individuals, presenting decreased or
increased levels of certain gut bacteria. In particular, they showed
reduced levels of good bacteria responsible for the overall benefits of
eating healthy foods. Similarly, Harvard researchers have found
considerable distinctions between the gut bacteria of people with MS
and without MS as well as between treated and untreated people with
MS.
Innovative companies throughout the U.S. are
developing microbiome-based treatments. Cambridge, Massachusetts-based
Evelo Biosciences is working on so-called monoclonal microbials –
isolated single strains of naturally occurring microbes that target
certain gut cells and thus initiate specific immunological responses
that can “modulate aspects of inflammation, neurodegeneration, and even
cancer”. Founded in 2014, the startup has recently raised $50 million
in venture financing, which will be used to advance various product
candidates, including immuno-inflammatory conditions, such as
psoriasis, rheumatoid arthritis, and certain allergies.
Also located in Cambridge, Massachusetts, Seres
Therapeutics is developing an oral microbiome therapeutic for the
treatment of inflammatory bowel diseases, a group of autoimmune
conditions that include Crohn’s disease and ulcerative colitis (UC).
SER-287 is currently being evaluated in a trial with people suffering
from mild to moderate UC. It aims to correct the dysbiosis found in the
gut of UC patients, expecting that, by treating the imbalance in their
microbiome, it will achieve meaningful clinical impact. Different from
traditional treatments available, the microbiome-based drug wouldn’t
work by suppressing the immune system, but rather reducing the triggers
of immune activation.
Vedanta Biosciences is another preeminent player in
the emerging market for microbiome-based therapies. Also located in
Cambridge, Massachusetts, the company was recently granted a U.S.
patent broadly covering “methods of treatment with therapeutics based
on bacterial spore fractions of microbiota obtained from human donors.”
Vedanta’s innovative technology aims to modulate pathways interaction
between the microbiome and the immune system. Ongoing work targets
conditions such as IBD, food allergies, and cancer immunotherapy.
Immunology and Cancer
Research
One of the hallmarks of cancerous cells is their
ability to avoid the body’s defense mechanisms. Aiming to overcome this
barrier, immunotherapy research has shown remarkable promise in
stimulating the immune system to find and defeat cancer. In fact,
immunotherapy has been among the most promising and rapidly evolving
alternatives for treating cancer.
When compared to traditional cancer treatments,
immunotherapy has often provided more durable control of tumor growth
and fewer side effects. While chemotherapy, for instance, kills both
healthy and diseased cells, immunotherapy enables the body to identify
and target only cancerous ones. Recent advances are very encouraging,
particularly when it comes to treatment-resistant and advanced-stage
cancers. The effectiveness of immunotherapy for hard-to-treat cancers
is increasingly evident, with positive results in a rapidly broadening
range of diseases.
Even though the prospect is very promising, further
research is necessary to understand why immunotherapy benefits have
been restricted to certain subsets of patients and certain types of
cancer. Cancer treatment vaccines are an important area of research
that can help shed light on potential ways forward.
Different from conventional vaccines, which focus on
prevention, therapeutic vaccines target those who have already been
diagnosed with the disease. Despite this difference, both types of
vaccines are based on the same premise – teaching the body’s immune
system to respond to a threat. In the case of cancer, this is
particularly challenging, as cancerous cells are, in fact, host cells.
For this reason, existing cancer vaccines have yielded varying results,
which seem to be correlated with the number of mutations in the
targeted tumor.
A growing number of experts believe that, in order
to be effective, cancer vaccines must be personalized. Recently
reported results from two clinical trials have shown great promise: in
one of them, eight out of thirteen melanoma patients were tumor free
after two years of being treated with a personalized cancer vaccine; in
the other, four out of six patients experienced similar results.
Customized vaccines take into consideration the fact that each tumor is
unique. They aim to maximize the chances of a strong and effective
response to tumor-specific antigens, called neoantigens.
Various innovative companies and research institutes
throughout the U.S. are involved in developing neoantigen-based
therapies. This is the case of Princeton, New Jersey-based Advaxis,
which recently received FDA approval for the first clinical trial of
neoantigen cancer vaccine ADXS-NEO. Developed in partnership with
biotech company Amgen, the innovative treatment uses a bacteria carrier
to deliver multiple neoantigens to the immune system as a means to
stimulate cell and antibody responses to the disease and hit multiple
targets at once.
Neon Therapeutics is also engaged in neoantigen
immunotherapy. The Cambridge, Massachusetts-based company recently
raised $70 million in funding for its cancer vaccine NEO-PV-01. By
sequencing a sample of a tumor, Neon identifies the mutations necessary
to develop a personalized treatment designed to prompt the most robust
immune response possible. The company has been making progress in a
multi-center clinical trial that combines vaccination with the
checkpoint blockade drug Nivolumab. This innovative strategy is
expected to further enhance the effectiveness of T-cells that target
specific neoantigens in advanced or metastatic melanoma, non-small cell
lung carcinoma, and transitional cell carcinoma of the bladder.
New Frontiers for
Immunology Research
Ongoing initiatives are beginning to clarify the
role of the immune system in a number of ailments that have not
traditionally been explored from an immunological standpoint.
Alzheimer’s disease, the leading cause of age-related dementia, is an
interesting example. Researchers at the University of California,
Irvine have recently demonstrated an acceleration in the development of
distinctive brain plaques associated with Alzheimer’s in mice that were
genetically modified to lack three key immune cell types, namely,
T-cells, B-cells, and NK-cells. When compared to a control group after
a period of six months, the genetically modified mice had up to twice
the level of beta-amyloid accumulation, which is a well-known hallmark
of Alzheimer’s.
UC Irvine neurobiologists believe that there is an
important interplay between immune cells in the blood (T-, B-, and
NK-cells) and those that reside in the brain, which are known as
microglia. After transferring healthy bone marrow stem cells into the
immune-deficient mice, they found that the reconstitution of the immune
system was accompanied by a boost in microglia’s ability to degrade
amyloid plaques. This finding could open the way for innovative
techniques to identify and even treat people at risk. It could also
clarify how the aging of the immune system contributes to the
development of Alzheimer’s.
Recent events have underlined the importance of
immunology research dedicated to the prevention of global epidemics,
such as Zika and Ebola. Even though numerous pharmaceutical
companies have engaged in the development of a Zika vaccine – the list
of companies includes Inovio Pharma, Themis, and Sanofi - none of their
ongoing efforts focuses on the immunization of pregnant women. Aiming
to close this gap and prevent the incidence of severe birth defects,
researchers at Washington University in St. Louis, the University of
Texas Medical Branch, and the National Institute of Allergy and
Infectious Diseases have successfully demonstrated the ability of two
potential vaccines to protect mice fetuses from infection.
Researchers from the University of Arizona have also made progress in
the development of a plant-based Zika vaccine that could represent a
safer and cheaper solution, which would meet the needs of various
underdeveloped countries.
Conclusion
Immunology is an extremely diverse field of
research. Immunology-related R&D efforts are crucial to improving
the lives of those suffering from a wide range of diseases, such as
diabetes, lupus, RA, MS, etc. Particularly promising areas for
innovation include immunotherapy, microbiome research, and the
development of vaccines for emerging global threats. Innovative
companies investing in immunology research should take advantage of
R&D tax credits to increase their chances of success.
