Allison ORourke

Senior Research Paper

Cancer is a horrendous disease that tears a person down both mentally and physically. As
of now the only way to beat cancer is to have your body ravaged apart by toxic chemotherapy or
have your organs burned by radiation. And even if you go through these terrible treatments there
is no guarantee that the cancer will be eradicated. But what if there was a new way to cure cancer
with minimal damage? There is a new treatment that is less invasive and more effective in
fighting cancer, "You start with the person's T-cells from their blood, then you add magnetic
beads covered with proteins that make them grow. After that you use a virus to change a cell's
DNA, creating a receptor that attacks the cancer. You grow more of these cells, and when you
have enough remove the cells and put them back in the body"(Herper). Dr.June and Dr.Grupp are
Professors of Immunotherapy at the University of Pennsylvania's Perelman School of Medicine
in Philadelphia, and are the leaders spearheading this new research"(Boal). The new treatment of
the injection of a modified HIV virus is an extremely promising form of cancer treatment that
will transform the world of oncology.
Treatment
The new form of treatment is created by taking a patient's T-cells, which are the cells that
recognize cancerous cells in the body, and modifying their DNA by injecting them with a
modified HIV virus. The doctors decided to use this method because "researchers needed to
modify the patients' own T-cells by genetically engineering them to produce an antibody-like
protein that would sic them on the tumor cells. To do that, the researchers needed to get at the Tcells' genes. They found that the best way to get this process to work was to use
HIV"(Aravosis). They call these new T-cell are called serial killer cells because "we've seen for

every T cell that we genetically modify and put into a patient's body, it has the ability to kill up to
93,000 leukemia cells"(Porter). This allows the body to combat the cancer without having to
suffer the horrible side effects that chemotherapy and radiation present. The HIV virus they use
is modified so that it will not infect the patient with HIV but rather changes the DNA of the Tcells. They use this specific virus because HIV naturally seeks out the patients T-cells and binds
to them, then they inject their own DNA thus taking over the cell"(Aravosis).
Selection of Patients
The patients that are selected for the trials have absolutely no treatment options left for
them because most have relapsed multiple times. Researchers say that they chose these subjects
because the "patients that were treating on this clinical trial have absolutely no other options left
for them. These are patients who are unfortunately destined to die of the disease in a fairly short
amount of time" (Grupp). This treatment required a specific type of patient because of the unique
nature of the cancer. For the majority of patients they have tried a various number of other
treatment options but none of them have worked, "patients with relapsed and chemotherapyrefractory preB-cell ALL have a poor prognosis despite the use of aggressive therapies such as
allogeneic hematopoietic stem-cell transplantation 1,2 and bispecific CD19 antibody
fragments"(Grupp).
Adult Patients
As with everything in the world of oncology children and adults respond very differently
to treatments. When the study was concluded the outcome looked fantastic "the first 2 studies
include 12 adults with chronic lymphocytic leukemia (CLL), and thus far, 9 of the 12 have had
good responses to the gene transfer treatment. We have just concluded the initial study, and the

first patient we ever treated, in July 2010, remains in remission. Actually, 2 of the first 3 patients
we treated remain in remission, demonstrating that the results are durable" (Goodman).
Child Patients
The trials of children have yielded better results than the adult trials. At the completion of
the trials it was concluded that "In the children's study, led by Dr. Stephan Grupp at CHOP, 4 of
the first 5 children we have treated have had complete remissions. The results in children are
very exciting and beyond our expectations. The first child treated was Emily "Emma"
Whitehead. We reported results showing her complete remission at the 2012 meeting of
ASH"(Goodman). There were two patients in particular that were studied in great detail. In the
first case study "Patient 1 was a 7-year-old girl with a second recurrence of ALL. She had
received a diagnosis 2 years earlier. A remission with a negative test for minimal residual disease
had been achieved, then she had a relapse 17 months after the original diagnosis. She had a
second remission after reinduction chemotherapy, but the cancer recurred 4 months later, and she
did not have a response to further intensive chemotherapy, including clofarabine, etoposide, and
cyclophosphamide"(Grupp). Then in the second case study "Patient 2 was a 10-year-old girl
with ALL who had had a second relapse after undergoing transplantation of umbilical-cord blood
from an unrelated donor (HLA-4/6) 28 months after diagnosis and 10 months before CTL019
infusion. She had had graft-versus-host disease (GVHD) after the transplantation, which resolved
with treatment; she was not receiving immunosuppressive therapy at the time of her relapse. She
did not have another remission, in spite of multiple cytotoxic and biologic therapies"(Grupp).
Both children had a similar reaction to the treatment in that "Both children had an increase in
circulating lymphocytes and neutrophils in the 2 weeks after CTL019 infusion most of the
lymphocytes were T cells that expressed the chimeric antigen receptor"(Grupp). Essentially this

means that both children showed an increase of cancer fighting T-cells. These two patients were
later declared NEC and have been cancer free ever since.
Durability of the treatment
While not fully understood right now the treatment seems to be extremely durable
because the T-cells continue to recognize the cancer and help to fight it off before it becomes
serious again. The leading oncologists believe it will prove to be a more permanent solution "The
durability of this immunotherapeutic approach is unknown at this time. However, an adult with
leukemia treated at the University of Pennsylvania remains in remission 2.5 years after
treatment, according to Penn researchers"(Mulcahy). They believe that the effectiveness of the
treatment is preserved because "the t-cells are able to reproduce with the modified DNA so it
passes on the cancer fighting DNA. The fact that these cells can survive for so long and continue
to be biologically active really is quite remarkable to all of us (Porter).
Effectiveness on other cancers
Since the treatment has only been tested on blood cancers the potential for it to be used
on other cancers is unknown. Currently there is a lot of research to discover if there is any hope
for this treatment to cross over into other types of cancer Early-stage pilot trials are being
conducted in other cancers at the University of Pennsylvania, Memorial Sloan-Kettering Cancer
Center, MD Anderson Cancer Center, Baylor College of Medicine, and the Fred Hutchinson
Cancer Center. Animal models suggest that the treatment works in other cancers, but we are in
the very early days of learning whether it holds promise for non-B-cell blood cancers and other
cancers in humans" (Goodman). Even though much is unknown about the treatment doctors
have started working to develop the treatment for similar cancers "doctors have started using this
sophisticated immunotherapy in patients with non-Hodgkin's lymphoma"(Lapook) . The doctors

who are working to expand the treatment are very excited about the prospects this treatment will
bring "If this can be applied to multiple cancers, certainly it opens up a whole new avenue of
therapy for many patients" (Boyer).
Drawbacks of the treatment
While the treatment is very promising it also have some damaging side effects. One of
the most concerning side effects is "they destroy healthy B-cells as well as cancerous ones,
leaving patients vulnerable to certain types of infections" (Grady). This can be very detrimental
because it does damage their immune system which leaves them susceptible to harmful
infections. Along with destroying the B-cells "CAR T-cell therapy can cause several worrisome
side effects, perhaps the most troublesome beingcytokine-release syndrome. The infused T cells
release cytokines, which are chemical messengers that help the T cells carry out their duties.
With cytokine-release syndrome, there is a rapid and massive release of cytokines into the
bloodstream, which can lead to dangerously high fevers and precipitous drops in blood pressure.
Cytokine-release syndrome is a common problem in patients treated with CAR T cells"(National
Cancer Institute). While some of these side effects are very severe the treatments positives still
heavily outweigh the negatives. Quite a few of these side effects will be experienced with all
types of cancer treatment.
Conclusion
This new cancer treatment shows an astronomical amount of promise. As with any new treatment
there is still a lot of progress to be made, "just as we would with other treatments, we need more
experience. We don't know the optimal dose of T cells yet. This is more difficult to calculate than
for drugs that are metabolized, because the genetically engineered T cells proliferate once they
are reinfused into the patient. At the moment, it appears that we have to give a certain threshold

number of T cells to the patient"(Goodman). This treatment has given hope to those who had
given up any expectation of recovery, '"any time you have a completely new therapy that has a
50-percent complete response rate in patients who have failed every other type of therapy, that's
the home run,' said Boyer"(Boal). There is still a lot of work to be made on this treatment, but
with such strong potential this could be the saving grace for many condemned patients.