Wednesday, January 31, 2018
Sunday, January 28, 2018
Audrey Hepburn
"Good things aren't supposed to just fall into your lap... do your part first," Audrey Hepburn.
(Audrey Hepburn was a British actress, model, dancer and humanitarian. Recognized as a film and fashion icon, Hepburn was active during Hollywood's Golden Age; 1929-1993).
Galileo Galilei
"The Bible shows the way to go to Heaven, not the way the Heavens go," Galileo Galilei.
(Galileo Galilei was an Italian polymath. Galileo is a central
figure in the transition from natural philosophy to modern science and
in the transformation of the scientific Renaissance into a scientific
revolution; 1564 -1642).
Saturday, January 27, 2018
Where the Wild Things Are: CAR T-Cell Therapy
A rambunctious
child, Max, who has been ignoring house rules and arguing with his mother is appropriately
wearing his favorite wolf suit when his mother calls him a, “wild thing!”, and
is sent to his room without supper to learn his lesson.
Alone in his bedroom and filled with rage, Max imagines the walls of his bedroom
disintegrating and becoming a vast ocean. He quickly makes a sailing boat and
after a year in the ocean, Max finally lands on an unknown jungle filled with
beasts known as the ‘Wild Things’.
Max’s desire for adventure, danger, and a deep longing for friendship(s)
even if that means it must be with the ‘Wild Things’, it comes with no surprise
that when Max meets these large creatures ashore, he is un-phased by their frightening
features of sharp claws, large fangs, and great striking eyes.
Subsequently, our
protagonist, Max is unanimously declared the wildest creature of them all and
is made king. Max’s first decree as King is to, “Let the rumpus begin!” Here
the adventure truly begins as Max and the ‘Wild Things’ start dancing in the
moonlight, hanging from trees of the land, and run riot.
However, it is difficult to miss the significance of ‘supper’ and the
‘Wild Thing’s’ appetites which is weaved into these adventures that Maurice
Sendak maintains throughout the tale. And it is when Max smells his supper that
he decides to give up being King. Max realizes how much he misses his mother,
her love, and home.
This touching masterpiece and a forever classic children’s book by
Maurice Sendak that ‘Where the Wild Things Are’ that reiterates the importance
of ‘time outs’ for children. ‘Time outs’ are necessary for in a childhood so
that children can learn to deal with anger management, to channel the negative
energy (such as rage) into creative outlets, and ultimately face their true
self’s.
INTRODUCTION:
As of August
2017, the Food and Drug Administration (FDA) officially approved CAR T-cell
therapy as a treatment option for Acute Lympho-Blastic Leukemia (ALL) which is
the most common form of cancer to affect children diagnosed with cancer. This
treatment option will very soon also be available for adults with advanced
lymphomas.
Researchers,
however, caution that CAR T-cells and other types of ACT are not developed
enough to ensure the safety and effective outcomes in patients with solid tumor
growths such as breast and colorectal cancer. Different types of ACT are still
in development.
Cancer treatment
consists of 3 pillars (surgery, chemotherapy, and radiation therapy)
but, the combination of targeted therapy and specific medications has begun to
replace these pillars in the past 20 years. This approach works by applying
target cancer cells found in the body by detecting cells that have molecular
changes that are common in cancer cells.
Adoptive Cell
Transfer (ACT) collects and uses patients’ own immune cells to treat cancer.
This quickly emerging immuno-therapy tactic includes many varying other types of
‘ACT’ (i.e. “ACT: TILs, TCRs, and CARs”). Immuno-therapies are known to recruit
and strengthen patients’ immune system to attack tumors located in the body and
in the past few years has been considered as the ‘5th pillar’ of
cancer treatment.
CAR T-cell
therapy has been restricted to small clinical trials which focused primarily on
patients with advanced blood cancer. These treatments have earned the vast
attention and recognition of researchers and general public alike because of its
remarkable responses from both child and adult patient volunteers for whom all
other treatments stopped working.
BACKGROUND
INFORMATION:
Chief of the Surgery Branch in NCI’s Center for Cancer
Research (CCR), Steven Rosenberg M.D., PH.D., is the immunotherapy pioneer
whose lab results were the first to report successful cancer treatment with CAR
T-cells. It was only due to recent drastic developments in CAR T-cells and
other ACT approaches that have aided researchers to their breakthrough(s) in
better understanding these therapies. They also can better translate this new
knowledge into improving ways to develop and test therapy options.
T-cells make up the backbone of CAR T-cell therapy which
are known as the pillars of the immune system and that their key role is in
orchestrating the body’s immune response and killing cells infected by
pathogens.
CAR T Cell
Therapy Is a Type of Cancer Immuno-therapy that works with your immune system by
using your T cells (or fighter cells). It was created by adding a new receptor
to the human body’s T-cells which are part of the immune system. This receptor
is known as a ‘Chimeric Antigen Receptor’ or ‘CAR’. Once the body’s T-cell has
added CAR it is now officially a CAR T-cell.
T cells are crucial to the human immune system as they
release cytokines. Cytokines are chemical messengers that help stimulate and
direct the immune response. With CRS there is a rapid and massive release of
cytokines into the bloodstream that leads to dangerously high fevers and
precipitous drops in blood pressure.
Researchers explained that the presence of CRS is an
on-target effect of CAR T-cell therapy which at the same time demonstrates the
activity of T-cells working in the body. Like all cancer therapies, CAR T-cell
therapy can have troubling and fatal side effects. The most frequent side
effect is cytokine-release syndrome (CRS). The greater the severity of a
patients’ disease before receiving CAR T-cells, the greater the risk of
experiencing severe CRS.
Many patients whether they are children or adults, can
use standard supportive therapies including steroids to manage CRS. With the
recent gain of knowledge and experience on CAR T-cell therapy, researchers are
also learning how to apply this information to manage the more serious cases of
CRS.
Research team at CHOP noticed something unique in
patients experiencing severe CRS many years ago. The observation was that they
all had particularly high levels of IL-60, which is a cytokine secreted by
T-cells and macrophages (which causes inflammation and is the body’s immune
response).
With this
information, CHOP was able to perform therapies that treated inflammatory conditions
meanwhile approving drugs such as tocilizumab (Actemra) that blocks IL-6
activity. This approach was successful in rapidly resolving difficulties most
patients reported on experiencing. Since then, tocilizumab has become a
standard therapy for managing severe CRS.
Another possible
side effect of CAR T-cell Therapy of an ‘off-target effect’ is a ‘B-cell
aplasia’ which causes large amounts of B-cells to die off. On the surface of
normally functioning B-cells, CD19 are expressed on their surface(s) and
function to produce antibodies to kill off foreign pathogens.
Normally
functioning B-cells within the body can die from infused CAR T-cells too. To
compensate for all this cell death, patients must undergo a process known as ‘immunoglobulin
therapy’ which provides patients with the critical antibodies to fight off
infections.
Even more
recently, researchers discovered a fatal side effect which swells the brain or
creates a ‘cerebral edema’ that revealed itself in some of the volunteer
patients who were part of the larger trials. These larger studies were created
in the hopes of creating potential support from the FDA of CAR T-cell therapies
for patients with advanced leukemia.
It has been reported
that a company even stopped any developments referring to CAR T-cell therapy when
patients from their clinical trials died. The cause of death was due to treatment-induced
cerebral edema. Many other trails concerning CAR T-cell therapies have observed
no cerebral edema complications or deaths.
Other side effects (aka: ‘neuro-toxicities’) are misperception,
seizure-like activity which have been seen in most CAR T-cell
therapy trials. Almost all cases that reported such side effects lasted
for a short period of time and were reversible. It is speculated that these ‘neuro-toxins’
may be related to CRS.
These special
receptors allow the T cells to recognize and attach to an antigen (a specific
protein) on the tumor cells. The CAR T cell therapies are the furthest along in
development target an antigen found on B cells called CD19 yet. Once the
collected T cells have been engineered to express the antigen-specific CAR,
they are “expanded” in the laboratory into the hundreds of millions.
The final
step is the infusion of the CAR T cells into the patient (which is preceded by
a “lympho-depleting” chemotherapy regimen). If all goes as planned, the
engineered cells further multiply in the patient’s body and, with guidance from
their engineered receptor, recognize and kill cancer cells that harbor the
antigen on their surfaces.
The CAR on the
cell’s surface is composed of fragment-like synthetic antibodies. The areas used
affect how well receptors can recognize or bind to the antigen of tumor cell(s).
Although there are important differences between the discussed therapies, similarities
do exist as well.
Receptors depend
on stimulation signals from inside the cell to do their job. Each CAR T cell
has signaling and “co-stimulatory” domains inside the cell that signal the cell
from the surface receptor. This is how different domains used in trials or in possible
future treatment options can affect a cell’s overall effectiveness and function.
With time, advances
in the intra-cellular engineering of CAR T cells will improve artificially
engineered T-cells’ ability to produce an even larger quantity of T-cells.
However, this will only occur after its infusion into the patient (known as the
‘expansion’ part of the procedure) and subsequent longer survival period in the
body’s circulatory system (known as ‘persistence’).
The initial
development of CAR T-cell therapies has focused largely on ALL. Over 80% of
children with ALL can be found in their B-cells, this being a predominant type
of ALL, can be cured with intensive chemotherapy. Those who experience relapse
despite being treated with chemotherapy or receiving a stem cell transplant,
their treatment options are depleted to approximately none (leading cause of
death in childhood cancer).
In the body, CAR
T-cells function to find their counterpart pair(s) on cells so that they are
successful in attacking the existing tumor(s). Since the majority of CAR T-cell
therapies must use patients or hosts own cells to create cancer-fighting cells,
each therapy is made specific for each patient.
Although CAR T cell
therapies have shown promise in treating some forms of cancer, the side effects
vary from mild to moderate. Some patients have reported to experience sever,
life-threatening reactions. Please note, that all treatments have side effects
that vary from case to case and at times even be unpredictable.
Typically, cancer
treatment includes therapy where blood is first drawn from the cancer patient,
T-cells from the blood sample are separated, a disarmed virus is then used for
T-cells to begin producing their genetically engineered receptors located on
their surfaces. These receptors are known as ‘Chimeric Antigen Receptors’ or
‘CARs’. These receptors do not exist naturally and are only created when needed
(aka: they are “synthetic molecules”).
Dr. Carl June M.D. from the University of
Pennsylvania Abramson Cancer Center, led a series of CAR T-cell clinical trials
to explain this ‘synthetic molecule(s)’ phenomenon that is most commonly seen
in leukemia patients.
RESEARCH:
In an earlier trial that used CD19-targeted CAR T-cells,
patients’ signs of cancer all disappeared (a complete response). Out of the 30
total patients, 27 of them experienced this complete recovery with no
continuing signs of recurrence long after treatment was over.
These
breakthroughs gave researchers to possibility and the foundation needed for
larger trailExit Disclaimer of CD19 targeted CAR T-cell therapy. Many of the
patients who participated in the trial, had complete and long-lasting
remissions. Based on the trial results, FDA approved tisagenlecleucel in August
2017.
Pediatric Oncology Branch (or ‘POB’ for shot), has led
similar studies of which the results in trials where CD19-trageted CAR T-cells.
Terry Fry, M.D., who has been the lead investigator on several POB trials of
CAR T cells, believes in an optimistic future from the progress made with CAR
T-cell therapy in children with ALL.
CD19-targeted CAR T cells were initially tested in
adults. But, it was the agency’s decision to approve the new therapy for
children and adolescents with ALL before adults that left many in the
scientific world stunned as this is an ‘unheard of’ action. Nevertheless, this
has been a true turning point moment for ALL patients.
There is no shortage of promising data
on CAR T cells used to treat adult patients with blood cancers. CD19-targeted
CAR T cells have produced strong results not only in patients with ALL but also
in patients with lymphomas. In a small NCI-led
trial of CAR T cells, primarily in patients
with advanced diffuse large B-cell lymphoma, more than half had complete
responses to the treatment.
The data provides a true glimpse of the
potential that this approach will have in patients with aggressive or advanced
lymphomas (as well as those who in the medical field typically are considered
‘virtually untreatable’).
The trial’s lead
investigator, James Kochenderfer, M.D., of the NCI Experimental
Transplantation and Immunology Branch. Since then, larger trialExit
Disclaimer studies were conducted with the primary focus on developing
ACT-based therapies which have officially proven and confirmed earlier results.
These observations are expected to help support FDA’s approval of Kite Pharmaceuticals
(who are working with NCI to make these discoveries)’ product for specific
patients with lymphoma.
The results in lymphoma to date have been incredibly successful and CAR
T cells are almost certain to become a frequently-used therapy for several
types of lymphoma. The rapid advances in and growth of CAR T-cell therapy has
exceeded the expectations of even those who were early believers in its
potential. Cohorts of patients who would have been considered terminal and are
now in a stable condition, durable, and are progressing in meaningful
remissions are leading quality life of up to 5 years.
CONCLUSION:
CAR T cell research is ongoing with the majority focused on
blood cancers and solid tumors. Five years ago, only a couple of trails existed
compared to today’s 180 plus. Most of today’s trials have used CD19-targeted
CAR T cells, but this too is quickly changing. Ever since the biopharmaceutical
industry has become personally invested in the research, the number of clinical
trials testing CAR T-cells have increased dramatically as a result.
Some patients with ALL do not respond to the CD19-targeted
therapy and those who experience a complete response 1/3 of these cases had
their disease return within a year. Many of these disease recurrences have been
linked to ALL cells’ no longer expressing CD19, a phenomenon known as antigen
loss.
Researchers in NCI’s POB are testing CAR T cells that target
the CD22 protein, which is also often overexpressed by ALL cells. The first
trial of CD22-targeted CAR T-cells Exit Disclaimer of which most patients
treated had complete remissions even those whose cancer progressed after
initially having a complete response to CD19-targeted therapy.
Compared to cases with the CD19-targeted CAR T cells,
however, relapses after CD22-targeted treatment are not uncommon. There is a
lot of improvement to look forward to considering the durability of remissions.
A possible way to improve durability or at least stall
antigen loss (if not prevent it completely), is to simultaneously attack
multiple antigens at once. There are NCI researchers that are currently
developing T-cells to target both CD19 and CD22. CHOP researchers are also
testing a CAR T cell that targets both CD19 and CD123, another antigen commonly
found on leukemia cells. The hope is to trial test this new approach before the
end of 2017.
A possible way to improve durability or at least stall
antigen loss (if not prevent it completely), is to simultaneously attack
multiple antigens at once. There are NCI researchers that are currently
developing T-cells to target both CD19 and CD22. CHOP researchers are also
testing a CAR T cell that targets both CD19 and CD123, another antigen commonly
found on leukemia cells. The hope is to trial test this new approach before the
end of 2017.
Early animal
studies suggested that dual targeting can indeed prevent antigen loss. Antigen
targets for CAR T-cell therapy have been identified in other blood cancers including
multiple myeloma. Dr. Kochenderfer and his colleagues at NCI who are working
with Kite have developed CAR T cells that target the BCMA protein (a protein
found on almost all myeloma cells). Since earlier results from BCMA-targeted
CAR T-cell trials showed positive, Kite is moving forward with further testing
of these cells but in a larger trail.
There is some
skepticism that CAR T cells will have the same success in solid tumors. Finding
suitable antigens to target on solid tumors has been a major challenge for
researchers and may even prove to be too difficult in most cases. Efforts to
identify unique antigens on the surface of solid tumors have largely been
unsuccessful.
The overwhelming
majority of tumor antigens located inside tumor cells are out of reach for CARs
and can only bind to antigens on the cell surface. Results already seen in
melanoma cases leads scientists and researchers alike to strongly believe that
other versions of ACT may be better for treating solid tumors.
This is why
researchers are trying to treat such cases with CAR T-cells. Currently trials
are being conducted to target the protein mesothelin which is overexpressed on
tumor cells in some of the deadliest cancers known to man (pancreatic and lung
cancers). The protein EGFRyIII is present in almost all tumor cells in advanced
brain cancer patients’ glioblastoma. Unfortunately, early reports from these
trials have not reported the same success that has been seen with blood
cancers.
When dealing with
solid tumors and targeting the antigens, researchers have been using the approach
used with CD19 which some researchers like Dr. Brentjens believes will not work
in all cases. Dr. Brentjens also brings attention to another key obstacle when
dealing with solid tumors which is that the components of the microenvironment
surrounding them conspire to dull the immune response.
Therefore,
success against solid tumors may need a “super T cell” instead. This ‘super
T-cell’ will have to be engineered to overcome immune-suppressing
environment(s) of many advanced solid tumors. Teams of researchers from
Memorial Sloan Kettering are currently working on a CAR T-cell with the
properties mentioned above.
CAR T cells have gained most of the public’s attention
concerning cellular therapies involved with ACT approach. Other types of CAR
T-cell treatments should be mentioned that have shown promise from their small
clinical trials, including in patients with solid tumors. One such approach
includes using the immune cells that can go inside the environment and around
the tumor. This is known as tumor-infiltrating lymphocytes (TILs).
Researchers at NCI were the first to use TILs to
successfully treat patients with advanced cancer. The very first cancers to be
tested were skin cancers (aka: melanoma’s), cervical, and other(s). It
wasn’t until recently that NCI researchers developed an innovative tool for
identifying TILs to recognize cancer cells and the mutations specific to that
cancer. Many cases led to tumor regressions in individuals with advanced
colorectal-Exit Disclaimer and liver cancer.
Another approach involves engineering patients’ T-cells to
express specific T-cell receptors (TCRs). Parts of these synthetic antibodies
are used by CARs to recognize specific antigens on the surface of these cells
and ONLY on the surface. TCRs are
naturally occurring receptors that recognize antigens located inside tumor
cells.
Small pieces of these antigens
are shuttled to the cell surface and “presented” to the immune system as part
of a collection of proteins called the MHC complex. In conclusion, TCR T-cells
have been tested in individuals varying from a range of solid tumors. The
results have showed much promise in melanoma and sarcoma patients.
Other forms of CAR T cells with differing configurations are
currently being tested. One type of CAR T-cell therapy that is currently being
developed is using the immune cells of healthy donors instead of the patients
themselves. The idea behind this approach is to create a ‘so-called
off-the-shelf CAR T-cell therapies’ to be immediately available for use and avoids
the time-consuming process of manufacturing each therapy to tailor every
patient.
A French company known as ‘Cellectis’, has already launched
its own off-the-shelf CD19-targeted CAR T-cell product in the United States for
patients with acute myeloid leukemia. The trails are in their first phase but
it’s produce made using a gene-editing technology named ‘TALEN’ which has
already been used in Europe in addition to 2 infants with ALL (who had already
tried all other treatment options). Both infants responded positively to
treatment.
Numerous other approaches are under investigation.
Researchers have countless other approaches that they are investigating. Some
teams of researchers are using nanotechnology to create CAR T cells inside the
human body, developing CAR T cells with “off switches” as a means of preventing
or limiting side effects like CRS, and using the gene-editing technology
CRISPR/Cas9 to engineer T-cells more precisely.
There is still much progress to be done when considering the
current state/status of existing CAR T-cell therapies. When considering cases
that are high risk based on clinical factors and the potential behind CAR
T-cells as a treatment option for children with ALL, these patients were given
roughly 2 and ½ years before their disease reappearing after their initial
chemotherapy.
However, if early indicators implied that these individuals
who are high-risk did not respond optimally to chemotherapy, this treatment
would be stopped by his or her physician, and the necessary steps would be
taken to begin CAR T-cell therapy. In cases where high-risk patients respond
well to treatment would be spared another 2 years of chemotherapy.
Links:
[C] https://www.britannica.com/topic/Where-the-Wild-Things-Are-by-Sendak
(For more on this topic also visit: National Cancer; “CAR T Cells: Engineering Patients’ Immune Cells to
Treat Their Cancers was originally published by the National Cancer
Institute.”)
Screenshots By: http://www.fanpop.com/clubs/where-the-wild-things-are/screencaps (screencaps modified/edited by me)
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