Conquering-Cancer
In his 1971 State of the
Union address, President Richard M. Nixon urged the nation to
turn “the same kind of concentrated effort that split the atom
and took man to the moon” towards conquering cancer. Over
four decades later, the lunar landing reference is again tied to
the battle against cancer through the launching of the National
Cancer Moonshot Initiative. Even though the analogy is the same,
the current level of knowledge about cancer is higher than ever
before. By understanding and tackling the complexity of cancer,
present-day efforts are bound to enable astronomical progress.
Published in January 2014,
our previous R&D cancer article was very well received by
readers as it presented an overview of important research
efforts at the time. So much innovation has occurred
since then, however, that we decided to write this follow-up
piece, which will explore recent developments in cancer research
and ongoing efforts to translate new scientific discoveries into
improved treatments.
The R&D Tax Credit
Enacted in 1981, the Federal Research and Development (R&D)
Tax Credit allows a credit of up to 13 percent 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 payroll taxes.
The Complexity of Cancer
Accounting for nearly 1 in every 4 deaths in the U.S., cancer is
the second most common cause of mortality in the country,
exceeded only by heart disease. The American Cancer Society
estimates that, in 2016 alone, there will be more than 1.6
million new diagnoses of cancer and approximately 600,000 cancer
deaths in the U.S.
Decades of research have
shed light on the complexity of cancer, which is now seen not as
one single disease, but as more than 200 different ones. It is
also known that most cancers are the result of multiple
mutations and that each patient’s tumor is unique. For these
reasons, it has become
that one therapeutic approach alone is not enough. On the
contrary, an effective strategy against cancer must rely on
advances in multiple fronts.
On February 1, the White
House announced a new $1 billion initiative to jumpstart the
National Cancer Moonshot efforts, which aim to double the rate
of progress against cancer, realizing a decade’s worth of
advances in five years. Led by Vice President Biden, the Cancer
Moonshot Task Force will focus on fostering collaborations and
enhancing Federal investments, targeted incentives, private
sector efforts, patient engagement initiatives, along with other
mechanisms designed to support cancer research and enable
progress in prevention, diagnosis, and treatment.
The future of cancer
research is certainly a multifaceted one. It is virtually
impossible to predict all the different and surprising ways in
which treatment and care will evolve. However, two important
trends will certainly be at the basis of innovation moving
forward:
Precision Medicine
The National Institutes of
Health defines precision medicine as “an emerging approach for
disease treatment and prevention that takes into account
individual variability in genes, environment, and lifestyle for
each person.” By acknowledging the complexity and
uniqueness of each patient’s condition, this personalized
approach to healthcare aims to overcome the notions of the
“average patient” or “one-size-fits-all medicine” and to
gradually create a new taxonomy of diseases in which they are no
longer defined by physical signs and symptoms, but rather by
their molecular and environmental causes.
In the case of cancer,
uniqueness is indisputable. Understanding the distinctive nature
of each patient’s body and the key genetic mutations behind his
disease is essential to identifying the most promising avenues
for treatment. By enabling the development of unique therapies
specially conceived to target the genetic abnormalities
involved, precision medicine gives new hope against
treatment-resistant and difficult-to-treat cancers.
Big Data
Access to massive amounts
of data opens the way for an unprecedented understanding of how
cancer evolves. Two aspects determine how big data can actually
benefit cancer research. On the one hand, there is a need for
high-performance analytics, which includes advanced software and
machine-learning capabilities. On the other hand, there must be
cooperation and enhanced sharing of data. The White House fact
sheet on the National Cancer Moonshot Initiative underlines that
“data sharing can break down barriers between institutions,
including those in the public and private sectors, to enable
maximum knowledge gained and patients helped.”
Built upon these two
overarching trends, the fields of immunotherapy and
next-generation genomic analysis stand out as promising areas in
cancer research. The following sections will present recent
advancements in both these domains.
Cancer Immunotherapy
Immunotherapy is arguably the most promising and rapidly
evolving alternative for treating cancer. Increasingly seen as a
potential new pillar of cancer therapy, this revolutionary field
of research is based on a simple strategy: harnessing the body’s
immune system to combat 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 in
immunotherapy are staggering, 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, including advanced melanoma, lung,
kidney, bladder, and head and neck cancers. Preliminary
successful results have also been reported for certain blood
cancers and glioblastoma, a particularly deadly brain cancer, as
well as for rare and intractable tumors caused by viruses. In
fact, ongoing clinical trials suggest that immunotherapy could
benefit more than two-dozen types of cancers.
Such a promising area of
research has attracted the attention of important
philanthropists. On April 13, tech billionaire Sean Parker
announced a $250 million grant to launch the Parker Institute
for Cancer Immunotherapy, which will bring together over 300
researchers working at 40 different laboratories in six U.S
institutions – Stanford, the University of California, San
Francisco, and University of California, Los Angeles, the
University of Pennsylvania, MD Anderson Cancer Center, and
Memorial Sloan Kettering Cancer Center. The partnership, which
will also involve patient advocacy groups and private companies,
aims to coordinate research efforts, removing the obstacles
related to bureaucracy and funding.
This is the largest
donation ever for cancer immunotherapy. It happened just a few
days after former New York City mayor Michael Bloomberg, Jones
Apparel Group founder Sidney Kimmel, and other philanthropists
announced a $125 million contribution devoted to create a cancer
immunotherapy research center at the Johns Hopkins University
medical school. The Bloomberg–Kimmel Institute for Cancer
Immunotherapy will gather more than 100 scientists and
clinicians from the immunology, genetics, microbiology, and
biomedical engineering fields. Research will focus primarily on
melanoma, colon, pancreatic, urologic, lung, breast, and ovarian
cancers.
The following paragraphs
present an overview of recent advances in five different areas
of immunotherapy research.
Checkpoint Inhibitors
Immune checkpoints work as
“immunological brakes” that help the body control immune
responses in order to limit the unwanted and dangerous
consequences of overreactions, such as excessive inflammation
and autoimmune disorders.
By producing these same
molecules, some tumors “push the brakes” and trick the immune
system into not properly responding to the disease. Immune
checkpoint inhibitors are designed to prevent tumor-induced
brakes, restoring the immune system’s ability to attack cancer
cells.
There are currently three
checkpoint inhibitors available on the market. They have enabled
unprecedented results in treating some advanced-stage cancer
patients, considerably increasing their life expectancy and
avoiding relapses.
Released on April 17,
long-term follow-up survival data for Bristol-Myers Squibb Co.’s
checkpoint inhibitor Opdivo showed that more than a third of
advanced-melanoma patients participating in the trial have
survived at least five years. According to the National Cancer
Institute, only 16.6 percent of advanced-melanoma patients lived
that long between 2005 and 2011. In other words, immunotherapy
has more than doubled the survival rate.
These results attest to
the effectiveness and durability of immunotherapy for some
patients, even those resistant to conventional treatments.
Opdivo was approved by the FDA in 2014 and can be used to treat
both melanoma and lung cancer. It targets a “brake” called PD-1,
which prevents T cells from fighting cancer. F. Stephen Hodi,
director of the Melanoma Center at Dana-Farber Cancer Institute
and an investigator at Harvard Medical School's Ludwig Center
points out that “The data provide a foundation for using
anti-PD-1 drugs as standard treatment for melanoma patients […].
Hopefully this would translate to other cancers as well.”
Cancer cells can also
suppress immunological responses by turning off T cells, the
“foot soldiers” in the battle against cancer. They do that by
pushing a “brake” located on the surface of such cells, a
protein called CTLA-4. Researchers at Baylor College of Medicine
have recently discovered that, contrary to what was previously
thought, CTLA-4 is not only present on T cells and other cells
of the same lineage, but that it is also produced and secreted
by antigen processing cells called dendritic cells.
Dendritic cells work as
“generals” that direct T-cell activity. The study revealed that
CTLA-4 has the power to turn off dendritic cells and prevent
them from activating T cells. In the words of William Decker,
senior author, “These results are relevant to the battle against
cancer because we showed that dendritic cell CTLA-4 performs a
very critical regulatory function. Its presence inhibits the
generation of downstream anticancer responses, whereas its
absence permits robust priming of such responses.”
A better understanding of
dendritic cell CTLA-4 is expected to shed light on more
effective combination therapies against cancer. A promising
example is yet another checkpoint inhibitor developed by
Bristol-Myers Squibb Co. called Yervoy (ipilimumab), which has
been used to treat melanoma patients by binding to CTLA-4 on T
cells and blocking the cancer signals that turn them off. Baylor
College researchers argue that recent findings provide a strong
rationale to use Yervoy “in new and better ways, for instance in
conjunction with cancer vaccines.”
A recent report by
Research and Markets predicts that the immune checkpoint
inhibitors market will become a multi-billion dollar market over
the upcoming decade with an expected annual growth rate of 27.7
percent. According to the report there are 26 novel checkpoint
inhibitor drugs in clinical in clinical development.
The untapped potential of
the checkpoint inhibitors market has attracted major
investments. In April 2015, Swiss drug maker Roche established a
$555 million partnership ($25 million upfront and $530 million
tied to milestones) with India’s Curadev Pharma for the
development of IDO1 and TDO inhibitors. This was just a
few months after Roche’s subsidiary Genentech agreed to pay $150
million upfront and potentially $1 billion tied to milestones in
a collaboration with Ames, Iowa-based NewLink Genetics also for
the development of an IDO inhibitor.
Bispecific T-Cell Engagers
Responsible for seeking
out and destroying targeted invaders, T-cells play a central
role to the body’s immunity. In the battle against cancer, some
immunotherapy approaches focus on facilitating the work of these
valuable combatants.
Bispecific T-cell engagers
(BiTEs), for instance, help the immune system identify and
attack malignant cells. With two different and simultaneous
targets, these modified antibodies serve as mediators that
redirect T cells towards tumor cells thus enhancing tumor
destruction.
Amgen’s Blincyto
(blinatumomab) is a BiTE antibody construct designed to treat
patients with acute lymphoblastic leukemia (ALL). Programmed to
attach itself to two different proteins in white blood cells,
one located in malignant B cells and the other in cancer-killing
T cells, the antibody places T cells within reach of targeted
cells thus facilitating their work.
In 2014, the FDA granted
Blincyto breakthrough therapy designation, priority review, and
orphan product designation due to preliminary clinical evidence
that the drug would offer a substantial improvement in safety
and effectiveness over available therapies targeted at a serious
and rare condition.
On February 4, Amgen
announced that a study demonstrated an overall survival benefit
for relapsed and refractory ALL patients treated with Blincyto.
This will allow the company to seek full approval from
regulatory authorities.
Modified T-Cell Therapy
Chimeric Antigen Receptor
(CAR) T-cell therapy can be generally defined as an attempt to
reprogram the patient’s immune cells to target specific cancer
cells. A sample of the patient’s T cells is collected from the
bloodstream and genetically modified to incorporate sensors, or
antigen receptors, that can seek out certain cancers. When
infused back into the patient, these engineered cells target and
destroy cancer cells.
Early experimental trials
of CAR T-cell therapy for blood cancer have shown extremely
promising results. According to British newspaper The Guardian,
94 percent of ALL patients went into remission and patients with
other types of blood cancer had response rates greater than 80
percent, half of which saw symptoms disappear entirely.
Though most studies thus
far have focused on hematologic malignancies, recent findings
suggest that t-cell immunotherapy could also be used to combat
solid tumors. Researchers from Penn Medicine and Harvard
University recently reported the success of a phase 1 study that
used CAR T-cell therapy against glioblastoma. Genetically
modified to target a tumor-specific protein, T cells used in the
study were capable of safely migrating to and infiltrating
tumors “even crossing the blood-brain barrier.”
Studies have also
suggested the existence of “memory” T cells that remain in the
patient’s body for two to 14 years after the treatment. If
confirmed, these persistent cells could translate into a
long-term, living defense against cancer.
Even though there have
been remarkably positive results, modified T-cell therapy is
still considered an effort of last resort due to the risk of
dangerous side effects, such as cytokine release syndrome, a
life-threatening, systemic inflammatory response. Further
research is necessary to mitigate risks and allow for a more
widespread application of this innovative treatment.
Cancer Treatment Vaccines
Different from
conventional vaccines, which focus on prevention, treatment
vaccines target those who have already been diagnosed with
cancer. By introducing antigens into the body, they stimulate
the activation of T cells or the production of antibodies that
will find and attack cancerous cells.
Numerous pharmaceutical
and biotechnology companies are currently working on cancer
vaccines. Headquartered in Durham, North Carolina, Heat
Biologics is the creator of a pioneering line of cancer vaccines
called ImPact (Immune Pan-Antigen Cytotoxic Therapy), which have
yielded very promising results in early trials. ImPact
technology modifies human cancer cells into miniature pumps
that, once infused into the patient’s body, secrete a range of
cancer antigens that stimulate immunological response. Suited to
treat various types of cancers, ImPact is an allogeneic, or
off-the-shelf, immunotherapy that does not require invasive
procedures and does not have storage or production limitations.
Heat is currently conducting clinical trials for two
ImPact-based products, targeting bladder cancer and non-small
cell lung cancer, a potential $11 billion market. Combination Therapies
In an effort to maximize
the potential of immunotherapies, researchers are exploring
innovative combinations both with different immunotherapy
approaches and with traditional treatments, including
chemotherapy and radiation. Cancer Research Institute CEO Jill
O’Donnell-Tormey points out that success rates go up when
immunotherapy is combined with other medications and treatments.
Combination therapy allows for a more personalized approach
tailored to each patient’s needs.
One of the most well known
patients to resort to combination therapy is former President
Jimmy Carter, who tested cancer free just a few months after
being diagnosed with metastatic melanoma that had spread to his
liver and brain. His treatment involved surgery, radiation and
Merck’s immunotherapy drug Keytruda (pembrolizumab), which works
as a checkpoint inhibitor.
Even though recent
advances in immunotherapy are very encouraging, further research
is necessary to understand why benefits are restricted to
certain subsets of patients and certain types of cancer. Roy
Jensen, director of the University of Kansas Cancer Center,
recently compared this period for immunotherapy to the 1960s for
chemotherapy – "there is so much to do and to figure out. We're
just at the start of this."
Genomic Analysis
By
enabling the creation of a personal roadmap towards effective
treatment and prevention, innovative genomic testing promises to
open the way for the future of precision medicine. The
unprecedented volume of genetic data currently available to the
research community has enabled major advances in next-generation
genome sequencing, particularly for cancer-related applications.
Extensive DNA libraries have allowed for previously unimaginable
analyses, which can unveil new cancer biomarkers. Considerable
reductions in the time necessary to obtain results, which can
become available as soon as two days after the test, as well as
a decrease in costs involved are also examples of recent
progress.
Genomic profiling is at
the basis of so-called precision prevention strategies, which
focus on high-risk individuals with certain genetic
predispositions. These tests also allow for better-informed
treatment choices, which maximize positive outcomes, and shed
light on new and groundbreaking diagnosing tools.
Better-Informed Treatment Choices
It has been widely
demonstrated that a patient’s genetic profile directly
influences the propensity to develop certain conditions as well
as the likelihood of response to different therapies. Likewise,
the genomic testing of tumors can considerably reduce
uncertainties surrounding treatment choices. They enable doctors
to assess the probability of success before submitting patients
to expensive and strenuous therapies. When it comes to
immunotherapy, for instance, genomic analyses are key to
understanding why some patients present remarkable results while
others are non-responsive.
Aiming to predict the
effectiveness of immunotherapy in brain cancer patients,
researchers at the University of California, Los Angeles have
created an innovative method that tracks changes in the immune
response. They use advanced T-cell receptor sequencing to
monitor the presence of biomarkers in T cells present both
within the tumor and in peripheral blood throughout the
treatment. The study has pioneered the use of high-throughput
sequencing to track systemic T-cell receptor expression. Initial
results showed that the level of T-cell infiltration in the
tumor could be a good indicator of extended survival rates.
In a similar effort,
immuno-oncology biotechnology company BriaCell, creator of
cancer therapeutic vaccine BriaVax, recently discovered a set of
genes, or “gene signature”, that can potentially explain
exceptionally positive results obtained in a clinical trial
subject with stage IV breast cancer. The whole-cell vaccine is
derived from a human breast cancer cell line and designed to
secrete an immune system activator that generates strong T-cell
response.
On April 12, BriaCell
announced the filing of a provisional patent application
“outlining certain features thought to improve clinical efficacy
of whole-cell cancer vaccines.” Based on the recently discovered
gene signature, the company plans to create BriaDx, a companion
diagnostic test designed to identify patients that are likely to
benefit from BriaVax.
Next-Generation Monitoring and Diagnosing
According to a July 2015
Grand View Research report, the next-generation sequencing
market will reach $27.8 billion in 2022. Advancements in
genomic sequencing will likely be the basis of next-generation
cancer diagnosis, which is expected to register a compound
annual growth rate of 32 percent between 2015 and 2022, reaching
$20.25 billion in the end of this period.
The work of David Zhang,
leading bioengineer at the Nucleic Acid Bioengineering
Laboratory at Rice University, is an interesting example of how
next-generation sequencing can lead to groundbreaking cancer
diagnostic tools. Zhang, who was recently awarded two National
Institutes of Health grants totaling $5.5 million, aims to
develop molecular capture probes that will facilitate the
detection of disease-causing DNA fractions that are very small
compared to the overwhelming majority of healthy DNA in a
patient’s sample.
By binding to healthy DNA,
which does not provide meaningful scientific or clinical
information, the customized probes effectively remove
unimportant sections of DNA and reveal unusual occurrences. If
successful, this effort could enable the development of
groundbreaking, rapid diagnostic tools for point-of-care
applications.
Advanced DNA sequencing is
also at the basis of innovative blood tests that could potently
revolutionize cancer care. Traditional biopsies are unable to
keep up with the rapid transformation of tumors, forcing doctors
to base their decisions on limited, outdated information. By
offering a more effective alternative to surgical and needle
biopsies, the so-called “liquid biopsies” open the way for new,
personalized therapies. Instead of analyzing tissue from the
tumor itself, this emerging technique allows for the
identification and analysis of DNA fragments that tumors shed
into the bloodstream.
These innovative tests are
the first noninvasive way to monitor cancer. They allow
doctors to profile genes and effectively target drugs to
mutations. They also provide a rapid and accurate assessment of
a treatment’s effectiveness, enabling more informed adjustments
as the disease evolves.
Though still in its
infancy, the market for liquid biopsies has outstanding
potential for growth. A February 2015 study by CHI Insight
Pharma Reports projects a 30 percent compound annual growth rate
for the five-year period beginning in 2015.
The rapidly growing number
of companies exploring this emerging technology attests to the
revolutionary potential of liquid biopsies. Redwood City,
California-based Guardant Health is the creator of the
Guardant360, an innovative blood test capable of detecting
changes in the genetic structure of cancer cells. When an
oncologist requests the test, Guardant sends out a kit for blood
drawing; the samples are sent back for targeted DNA sequencing
and results are made available in less than two weeks.
According to CEO and
co-founder of Guardant Helmy Eltoukhy, by January 2016, more
than 20 thousand patients had used the company’s test. Eltouky
estimates that the U.S. market for liquid biopsies could surpass
$20 billion a year.
Recent studies have
attested to the efficacy of blood-based biopsies. Researchers at
Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC) recently
developed a blood test that can detect mutations in two
important genes in non-small cell lung cancer (NSCLC).
Reliability levels were demonstrated to such an extent that
DF/BWCC decided to become the first medical facility in the
country to offer the test to all its NSCLC patients.
In addition to enabling
quicker results – only three days versus 12 days for tissue
biopsies in newly diagnosed patients and 27 days in
drug-resistant patients, the innovative test also proved highly
accurate. It demonstrated 100 percent predictive value for newly
diagnosed patients and was capable of identifying cases that had
not been detected during traditional biopsies.
By analyzing free-floating
DNA from cancer cells in the patient’s blood, the liquid biopsy
provides a “snap-shot” of genetic abnormalities. The detection
of mutations is key to enabling a personalized approach to
treatment, in which drugs targeted at specific mutations are
only administered to those who can actually benefit from them.
The procedure, technically
referred to as rapid plasma genotyping, shows great promise as a
clinical test for a variety of cancers. In the words senior
author of the study, Geoffrey Oxnard, MD, thoracic oncologist
and lung cancer researcher at DF/BWCC, “[It is] a rapid,
noninvasive way of screening a cancer for common genetic
fingerprints, while avoiding the challenges of traditional
invasive biopsies."
Researchers are hopeful
that future developments will enable the use of blood tests not
only as monitoring tools but also for very early cancer
diagnosis. In the words of Antonious Schuh, from San Diego-based
molecular diagnostic company Trovagene, "Why does there have to
be a tumor? The tumor is the symptom. The disease is the DNA.”
Conclusion
The
ambitious Cancer Moonshot Initiative comes at a time of
unprecedented hope. Major advancements in immunotherapy and
genomic analysis fueled by a personalized, data-driven approach
to cancer research make the “moon” seem closer than ever.
R&D tax credits are a strategic tool to support innovative
efforts in the war against cancer.
