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Annotated Bibliography
Theresa Miorin
Professor Campbell
UWRT 1103

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CAR T-Cell Therapy: Engineering Patients Immune Cells to Treat Their Cancers.
National Cancer Institute. National Institutes of Health, October 16 2014. Web. 3 March
2016
The National Cancer Institute is one of the leading stops for information concerning cancer and research steps taken for treatments. It is under the National Institutes of Health,
whose purpose is to inform and lead studies on diseases and other ailments that derail
human health.
This website provides information concerning T-Cell therapy and how a patients immune
cells can be utilized to treat their diseases. It builds off of and provides a more generalized group of information that was also included in the journal article about T-cell immunotherapy. Immunotherapy is therapy that utilizes a patients immune system to combat the disease, and is often called the fifth pillar of cancer treatment, behind surgery,
chemotherapy, and radiation therapy. In immunotherapy, an approach called Adoptive
Cell Transfer (ACT) can be used to recognize and attack tumors. There have only been
small clinical trials thus far, but have generated some response in patients with advanced
cancer. One such example is testing that involved acute lymphoblastic leukemia (ALL)
patients that had very little options left, but when using trials of ACT, had their cancer
disappear entirely and have remained cancer free. Despite the positivity, more trials are
still needed.
In Adoptive Cell Transfer, its building blocks are the T cells, which are a type of immune
cell found in the blood of a patient. The T cells become genetically engineered to produce specific receptors called chimeric antigen receptors (CARs), which are proteins that

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allow the T cells to recognize the antigen which is a protein. These would be grown in a
laboratory until they number in the millions. CAR T cells would be infused in the patient
and multiply to recognize and kill cancer cells that have the antigen. This kind of treatment would provide a new option for patients that wasnt present before.
After several trials, results have been found including one where 14 of 16 participants
experienced complete responses, some of which were only 2 weeks after treatment. Another included one where 15 participants either had complete or partial responses. Aside
from these positive results from the trials, side effects have been seen. One such side effect is cytokine-release syndrome, which is when there is a rapid release of cytokines in
the blood stream. The T cells release the cytokines because they are chemical messengers that help the T cells, but the massive release of them can cause high fevers and large
drops in blood pressure. The use of genetically engineered T cells is stilled deemed as
promising by several researchers at the National Cancer Institute and further trials are
being done.
Because of the large amount of basic information provided in this site, it would most definitely be a helpful source, especially if it were coupled with the Nature Reviews journal.
This website touches base on many of the topics discussed and even mentions several trials done, as well as what precautions were taken if there were missteps in the process,
such as the cytokine-release syndrome. The information provided is reliable as well because it is under the National Institutes of Health, whose information comes from solid
research that is being done by experts in that particular field. The research provided from
the National Cancer Institute is even under the United States Department of Health and

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Human Services, so the research and information provided by the NCI must be solid research that provides promising results after several trials. Because the website also discusses where problems occurred and what steps were taken to resolve the problems, such
as the disease, it ensures that precautions are being taken in the procedure as well as ensuring the transfer of T cells will be a beneficial treatment options for patients with cancer. The one downside to this website is that the information provided on the page was
last updated in October of 2014, so the information is not as recent. But if used as background information to bolster other sources with more updated information, then it will
be helpful and will be used in the project.

Darcy, Phillip K., Michael H. Kershaw, and Jennifer A. Westwood. Gene-engineered T Cells
for Cancer Therapy Nature Reviews: Cancer Volume 13 (August 2013): p. 525-541.
Web. 2 March 2016
The authors of this article are all researchers in Australia who study cancer, more specifically immunotherapy involving T cells. Michael H. Kershaw received a Ph.D. from the
University of Melbourne for his studies in genetic redirection of T cells against cancer
and now leads the Immune Innovation Laboratory at the Peter MacCallum Cancer Center
in Melbourne, Australia to study the advance in the immune system and cancer. Jennifer
A. Westwood received a B.Sc. Honors degree from the University of Melbourne and has
spent time at the National Cancer Institute in Maryland. She currently is working at the
Peter MacCallum Cancer Center as well where she is investigating T cell function against
tumors. Phillip K. Darcy is a Senior Research fellow and head of the Cancer Im-

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munotherapy Laboratory at the Peter MacCallum Cancer Center where he is a world
leader in adoptive T cell immunotherapy due to his development in preclinical mouse
models of cancer and the translation into patients.
Their research together led to the creation of this section in the journal, which discusses
the capacity of T cells to eradicate diseased cells; however, there are challenges that can
render the T cells ineffectual. There are several hundred billion T cells that reside in typhoid tissues and circulate throughout the bloodstream. The T cell receptors mediate the
recognition of and responses to diseased cells, and an antigen is presented by the MHC,
or the major histocompatibility complex. One method for T cells use is the ACT, or
adoptive cell transfer. This is when tumor-specific T cells are isolated from tumor-infiltrating lymphocytes (TILs) followed by their activation and expansion in vitro before reinfusion back into the patient. But problems occur with this process when many tumor
cells used reduced antigen processing or MHC expression to render the T cells blind to
their presence. The growth factors and immunosuppressive compounds can be co-opted
from the macrophages or granulocytes to support the tumor grown and down regulate the
immune activity.
Another form of treatment is having T cells responds to Tumor Associated Antigens
(TAAs), but they are often rendered unable to respond due to immune tolerance. The tumor specific T cells are either deleted or non-responsive to self molecules, including the
TAAs. These cannot be isolated. In this treatment, genetic engineering is used to insert
the T cell genes encoding cell surface receptors that can detect the TAAs. If the affinity
of the TRC for the TAA is increased through the enhanced activity of the the TRC gene-

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modified cells, all that is needed to be done is changing the amino acid composition of
crucial TRC antigen binding regions. This results in increased anti-tumor T cell responses by more than fourfold and can be harnessed against tumors; however, some specificity
against tumors can be lost due to activity against similar amino acid sequences in normal
cells. For complete immune eradication diseases, the tumor microenvironment must support immune activity. The microenvironment of tumors is often immunosuppressive due
to the lack of regulatory cells that can mediate immune suppression.
Several trials had been done in this research including TRC clinical trials. This was the
use of human T cells transduced with an anti-MART1 TRC trans-gene that was isolated
from TILs from patients with melanoma. They sustained objective responses in four of
the thirty-one patients involved. There was also evidence that gene-engineered T cells
could induce objective responses in patients. Further trials in solid cancer settings involved therapeutic responses indicated from the T cells modified with an anti-CEA TRC
isolated from HLA-transgenic mice. The toxicity against normal intestinal epithelial cells
led to severe colitis in all of the patients that resulted in the cessation of the study. This
highlighted the potential of the approach but raised awareness of the potential for toxicity
associated with the ACT of TRC gene-modified T cells. Effective immune response
against cancer can be done by gene-engineering strategies by enabling T cells to recognize and respond against tumor cells as well as facilitating trafficking to tumors and persistence for long periods. This isnt optimal for all cancer types and improvements will
need to be made. The expression of TAAs can be lost on a proportion of tumor cells, but

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using several TRC or CAR genes that target multiple TAAs simultaneously may be more
effective.
The qualitative research found in the work done at the Peter MacCallum Cancer Center
by these three cancer immunologists has proven to be intellectual evidence that is solid in
the study of tumor suppression involving T cells. It incorporates background knowledge
needed to understand the research done as well as the outcomes of different trials involved in the studies. There is no bias in the journal, just pure scientific research done to
enhance the study of immunology for others who plan on either researching further into
the field or wish to learn more information on what actions are being taken. The information provided was clear and concise, and will be referenced throughout my Inquiry
Project due to its valuable information that is provided throughout, especially the sections
devoted to the actual trials done on patients and what the outcomes were.

Sharpe, Michaela and Natalie Mount. Genetically Modified T Cells in Cancer Therapy:
Opportunities and Challenges. The Company of Biologists. The Company of Biologists
Ltd (2015): p. 337-350. Web. 6 March 2016
This article continues on the subject of T cells, but it begins to delve into the efficacy and
safety of the trials and treatment using T cell immunotherapy. A factor that influences the
efficacy following the T cell therapy is that the cancer cells can lose expression of the
targeted antigen. Also, factors present in the tumor microenvironment can affect the Tcell based immunotherapies. This microenvironment consists of tumor cells, immune
cells, and has an immunosuppressive environment that affects antigen presentation. The

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tumors also have T Regular Cells that reduce the activity of tumor-specific T cells. All of
these factors lead into the effectiveness of the T cell therapies.
When determining the safety of the T cell therapies, the most critical are on-target offtumor activity, off-target reactivity, and cytokine-release syndromes. Genetically modified T cells could trigger a potent cellular immune response against tissues of the body,
even those at low levels. This is the on-target off-tumor activity because it is present only
on tumor cells and not on normal cells. There has been depletion of normal B cells, but
there is difficulty in identifying tumor-specific targets because the peptide sequence in the
cells can be found in other proteins. The off target reactivity has been recorded in clinical
trials just like the on-target off-tumor activity. This is a risk for genetically modified
TCR T cells, which could possibly react against peptides in proteins other than the targeted ones. The pre-clinical studies have demonstrated the TRC mispairing having the potential to induce the harmful recognition of self-antigens. Cytokine-release syndrome has
also been reported in T cell therapies. These therapies can be effective when inducing
tumor cell lysis and tumor cell removal at a faster rate, but this faster rate results in high
levels of cytokine release, which causes high fevers, rigors, nausea, and diarrhea.
Despite these faults, there are strategies to improve on the current T cell based therapies.
These include overcoming particular challenges such as appropriately activating the T
cells upon antigen recognition, counteracting the immunosuppressive effects of the microenvironment in the tumor, and identifying the antigens. For T cell activation, the tumors often present antigens which can result in exhausted T cells that have reduced function and capacity. The tumor environment also can induce an up regulation of T cell co-

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inhibitory molecules. By ensuring the minimization of the TCR and the TCR expressed
by the T cells, the mispairing could reduce the ability of the cells to interact with a desired peptide and increase a risk for autoimmunity. To counteract the immunosuppressive
effects of the tumors environment, the balance of the number and activation state of immune effector T cells versus the number of suppressor cells must be addressed. Secretions of certain peptides from the T cells can promote resistance to inhibition and lead to
enhanced T cell activity.
These areas can be focused on in further clinical trials to create new advances in the field
of T cell therapies. As challenges are found, the ability of the desired anti-tumor effects
as well as the identification of antigens is being addressed where the clinical data can
possibly lead to therapies being used, as long as they are on a salable and cost-effective
manufacturing system. This article touches base on all of these topics and more as it discusses what T cell therapy is and what the different challenges facing this immunotherapy
could be. Other articles had briefly mentioned drawbacks in T cell therapy, but this one
spent a majority of the article discussing what the challenges are and how they can possibly be altered and fixed in order to enhance the use of T cell therapy. Because of the
credible authors who have advanced degrees in the area of cancer immunotherapy and
research, the information regarding what is found in the article as well as the other
sources they included to backup their information makes it a more reliable source. It is
an article that discusses the T cells with sound evidence and research backed up by trials
performed and the research done by others who are studying immunotherapy in T cells.
Because of the extensive amount of information as well as the sections discussing the

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challenges posed by T cell therapy, this article will be used in the final research paper to
provide more facts and figures on the true effect of T cell immunotherapies and whether
the positive outcomes can outweigh the challenges and side effects of the therapy.

Stein, Rob. Harnessing the Immune System to Fight Cancer. National Public Radio. Feb
2015. Web. 7 March 2016
This article discusses a woman named Barbara Marder, who had been diagnosed with
lung cancer and went through rounds of chemotherapy for treatment. Later on during a
routine scan, the cancer was found again in her lung. In order to keep fighting, she began
to explore other options where the idea of immunotherapy was brought up. In this specific article, it discusses checkpoint inhibitors, which is another form of immunotherapy not
discussed in the other sources. This provides an additional counter form for the research
in order to discuss alternatives and to see which therapy is more promising.
Checkpoint inhibitors are drugs that prevent cancer from becoming invisible to the immune system. Cancer cells can trick the normal immune response by sending out a
checkpoint signal call either PD-1 or PD-L1, which deactivates T cells. The inhibitors
will block the PD-1 or PD-L1 by turning the T cells back on. There has even been several studies that Marder participated in, and promising results ensued when the tumors in
her left lung began to disappear. There are side effects to the inhibitors, however, such as
causing the immune system to attack healthy cells, which can often cause serious organ
damage that can be life threatening. There are smaller side effects such as drowsiness

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and itchy rash, but not too far fetched from what normal chemotherapy would cause in
side effects.
While studying the areas of immunotherapy, people begin to wonder how long they will
last and their effectiveness. This article begins to discuss some aspects, such as the inhibitors seeming to keep going on longer, even in patients who stopped responding to the
methods of chemotherapy. There have even been survival rates higher than what was expected in lung cancer patients. One large downside is the cost, which is more than
$120,000 a round for the drug. This article touches base on the high price and how people wish for the prices to be cut, but provides no specific details into what is being asked
or what could possibly be done to cut the cost of the treatment. It even leads into the
conclusion that the T cells will remember how to attack the tumor and eventually will no
longer need the treatment since the immune system can remember the process of attacking those specific cancer cells.
NPR, or National Public Radio is a news source for a variety of articles and information
and can often be deemed as reliable. This source does provide many interesting aspects
of immunotherapy and does begin to discuss some information regarding T cells; however, there are many questions left unanswered and it is not a very scholarly article when it
comes to the information provided. If this were to be used in the research paper, it will
be utilized as a form of public opinion and additional source outlook in order to give an
outside view with a specific patient involved.