Product Proposal

Introduction + Statement of Purpose

I have held an interest in oncology for many years and for many reasons. Firstly, I

was only eight when my beloved aunt contracted a form of pulmonary cancer, and I was

mystified about how a simple misbehaving cell could so much pain to my family. However,

when I read the best-selling novel Cancer: An Emperor of All Maladies by oncologist Dr.

Siddhartha Mukherjee, I realized that cancer is much more complicated than just

continuous cell division. Furthermore, I became acutely aware of how widespread this

disease is, meaning that the majority of individuals have either experienced the physical

difficulties that my aunt had or at least lost a loved one like my family has. With this, I am

motivated to do my part in the industry to both research the terminal disease and first-

handedly give patients their best chance of survival as a medical oncologist.

Although I had these two goals in mind, for my first year of the Independent Study and

Mentorship program, I decided to pursue biomedical engineering as my topic of choice to

explore the research aspect of the medical field. However, it was clear to me that

bioengineering had many applications in the oncology field. In fact, I dedicated my original

work and product last year to conduct a statistical analysis of how methylation in the

MGMT promoter region affected response to chemotherapy in glioblastoma patients.

Acquiring a methylated MGMT promoter region in the DNA is based on genetics, and as my

mentor and I confirmed through my original work, it is a predictor of better response to

chemotherapy. I was able to bypass HIPAA laws and patient confidentiality issues by

obtaining imaging and clinical data from the Cancer Imaging Archive– available for public

use. I specifically used the database IVY_GAP which tracked seventeen glioblastoma
patients through two years of treatment. I then utilized the imaging software OsiriX to

comb through the hundreds of tumor images for each patient and track both the necrotic

and full tumor areas. Converting the imaging data to this usable format, I used the

statistical software MatLab and R to create modeling graphs and conduct a T-test to

determine statistical significance in the differences among methylated MGMT and non-

methylation MGMT patients.

Conducting a cancer related original work reinforced my interest in the disease and

created an easy transition into studying oncology for my second ISM year. In my pursuit of

the oncology field, I found a constant theme in all my research and professional meetings:

the idea of innovation. This connection between the bioengineering basis of discovery and

oncology’s constant innovation was not clear to me at first, but throughout the year I

learned that oncology is constantly changing. Each research article I read has usually been

updated within the past month or two with the more up-to-date and accurate data. New

and more efficient treatment types are discovered each and every day, and oncologists

have to keep up with these publications to be the best doctor they can for their patients.

Learning about the significance of cancer research within oncology field made it clear that

my original work should encompass a research component. However, I wanted to diverge

from what I worked on last year so I would be able to obtain a variety of experiences. The

thing about the medical field is that you do not need to be a researcher to conduct research.

Rather than conducting academic studies, most oncologists partake in clinical research in

which they administer new treatments to their patients and then note the effects.

My mentor Dr. Anil Bhogaraju and I decided that for my original work this year, I

would analyze his patients’ clinical data of their responses to immunotherapy. Specifically, I
will see if these patients have any immune-related adverse events (irAEs) from taking the

PD-1 blocking drugs Opdivo and Keytruda. With my learnings, I hope to write a research

paper to add to the archive of immunotherapy research online. This original work will

correspond well with my work throughout this year in which I learned about different

forms of immunotherapy through personal research and genetic lectures. Not only will

analyzing immunotherapy allow me to compile my studies of the year but will also expose

me to the clinical side of research I will participate in when I become an oncologist.

Contrasting the academia-based research I conducted last year to the clinical research this

year will allow me to distinguish the two sides of the medical field and choose whether

being a scientist or doctor is better for me. In addition, as a result of the fast-changing

nature of the oncology field, I hope to create a website that updates major breakthroughs in

the oncology field. At first, this website was targeted to oncologists, but I then realized that

most oncologists are subscribed to cancer organizations that already provide updated

articles. Instead, I hope to target my website towards students and those interested in

learning more about cancer. Creating this website will allow me to keep up with oncology

news myself and find a use for the domain I own. All in all, my two-part original work and

product will allow me to display all the skills I gained throughout this year into a compact

scientific synthesis.

Review of Skills and Research

As with any medically related research, my original work requires an understanding

of certain chemistry and biology topics. Luckily, I have taken both AP chemistry and biology

which greatly facilitated my understanding of the content required to partake in this

project. To start off, I learned the logic behind immunology itself. Essentially, the body’s
immune system is able to fight off viruses and bacteria effectively to protect the individual

from easily becoming sick. However, cancer cells are part of the body itself and are able to

trick the antigen recognizing cells into bypassing them. With this, the body’s immune

system is unable to prevent tumor growth and cancer survival. Immunotherapy attempts to

stimulate the body’s immune system into fighting off cancer itself, providing a more natural

treatment than radiation or chemotherapy. There are countless types of immunotherapy

being developed from CAR-T which uses genetically engineered T cells to more common

immunotherapeutic drugs such as Arzerra and Opdivo. To understand these

immunotherapies is greater detail, I needed to study basic concepts of the immune system

and signal transduction pathways. With this, I had to read research papers discussing the

basics of how the immune system works and the key cell types required in keeping the

body healthy.

The core of tumor immunology are the cell types involved in tumor recognition and

rejection including CD8+ and CD4+ lymphocytes which are types of T cells involved in

initiating the distinction between body and foreign cells. These T cells are able to recognize

foreign particles by recepting antigens which are substances that can induce an immune

response. If they contact antigens that they do not recognize, these T cells can then

stimulate the immune system to destroy the foreign cells emitting the antigen. This process

of T cells such as CD8+ distinguishing between self- and non-self antigens is a result of the

CD8 receptor binding to the major histocompatibility complex (MHC) of the target cell. This

whole process of T cell recognition lies heavily on signal transduction pathways—the

body’s mode of communication— and is heavily regulated to work effectively for the body’s
survival. The workings of the immune system were crucial for me to learn in order to grasp

tumor evasion of immune surveillance.

The theory of the immune system’s influence on tumor progression is known as

cancer immunoediting which progresses in three steps after the body’s intrinsic tumor

suppression methods such as apoptosis and repair do not work. The first step is known as

elimination in which the immune system responses to tumor antigens and proceeds

normally to destroy the cancer cells. The next step is called equilibrium in which there is a

balance between the tumor cell destruction and the tumor cell growth. This essentially

means that the immune response is neither helping nor worsening the cancer conditions.

The last step is termed as an escape and is when the tumor is able to grow faster than the

immune system is able to destroy cells. Immunotherapy researchers attempt to understand

how the tumor evades such biological responses and then develops mechanisms to bar the

cancerous cells from bypassing the immune system. The main way that tumors are able to

escape the immune surveillance is by losing their MHC class 1 expression so that the

antigens that the T cells are able to recognize tumors with are not transported to the tumor

surface. Tumors are also able to manipulate cytokine levels which can increase infiltration

of Treg cells which reduce the proliferation of the CD8+ and CD4+ lymphocytes that would

recognize the tumor cells. The next mechanism that tumors use in evasion of the immune

system is the one that I will be working with my original work: upregulation of the

expression of immune checkpoint molecules such as PD-1 and PD ligand 1 (PD-L1) which

promote T cell exhaustion in the form of a negative feedback inhibition. PD-1 is a

transmembrane protein that works as an inhibitory molecule that binds to the PD-1 ligand

which is expressed on the surface of tumor cells. This PD-1 and PD-L1 interaction directly
prevents the apoptosis of the cancer cell and promotes conversion of T cells into Treg cells,

further slowing down the immune response against the tumor. The two drugs that I am

analyzing with this clinical trial, Opdivo (nivolumab) and Keytruda (pembrolizumab) work

as checkpoint inhibitors that produce antibodies that target PD-1 to block the signal that

would have prevented the T cell from attacking the cancer.

Although clinical trials have suggested success of the drugs against melanoma (skin

cancer), checkpoint inhibitor immunotherapy has many toxicities associated with it. Since

the aim of my original work is to analyze the side effects Dr. Bhogaraju’s patients develop

after taking Opdivo or Keytruda, I needed to research common inflammatory events

associated with immune-related adverse events (irAEs). Since the immune system is being

influenced, this can attack the normal cells as well. With this, irAEs include anything from

dermatologic issues to pneumonitis to fatigue. The occurrence of these irAEs depends on

genetics and specifics of a patient’s case so it is difficult to predict the side effects of a drug

without conducting clinical trials. Fortunately, most of these irAEs can be treated by

disruption of the drugs, discontinuation of the drugs, or the administration of

corticosteroid immunosuppression.

Understanding immune system basics, checkpoint inhibition, and the toxicities

linked with it were just the groundwork for me to start my original work; there is still

much more for me to learn in order to be successful with my original work. Firstly, for me

to accurately understand the side effects present in the clinical study, I need to research

and become familiar with the main side effects, particularly for Opdivo and Keytruda. I can

achieve this by finding the FDA approved drug papers for these PD-1 blocking drugs and

then specifically researching each irAE. This way, I can compare the results I obtain from
my original work with that of other clinical trials. Next, I need to learn how to write a

clinical trial formatted paper so my product can be as professional as possible. This can be

achieved quite easily as I have read many medical research papers and can attempt to

mirror the arrangement. The final major research I have to complete is finding reliable and

informative oncology news resources so I can compile the latest breakthroughs in oncology

research. I plan to tackle this part of my original work in two different steps. First, I will ask

my mentor about how he obtains his oncology news and subscribe to the same sources.

Along with this, I noticed that Scientific American constantly writes cancer research articles

so I will look into the oncology sources the magazine refers to. In general, my learnings

from my mentorship throughout this year have been the most impactful in helping me

move forward with my original work, but I still have much more to discover.

Methodology

1. Finalize initial research to begin actively working with patient data: Dr.

Bhogaraju printed me two articles titled Principles of Cancer Immunotherapy and

Toxicities Associated With Checkpoint Inhibitor Immunotherapy which are both

written by medical professionals and explain the core of my original work research

thoroughly. After analyzing these research papers, I can confident in analyzing my

original work data.

2. Schedule a mentor visit to determine with Dr. Bhogaraju if the data from forty-

five patients is sufficient in completing my original work: Ms. Anderson, Flower

Mound Texas Oncology’s clinical research coordinator had compiled some patient

cases for me to use for my project. This mentor meeting will allow me to become
 familiar with the parameters of the data for further plan for the format of my

original work.

3. Send a thank you card to Ms. Whitney Anderson for helping with my original

work: Ms. Anderson has been extremely kind to me in my mentorship and I hope to

show my gratitude for her help.

4. Determine the irAEs experienced by the patients and the frequency of

occurrences: This can be accomplished by observing the data and noticing if

common irAEs (dermatologic, hepatitis, etc.) are present. Also, note the uncommon

irAEs occur and the percentage of incidence for each type of observed side effect.

5. Note if there are any correlations among patient parameters and

susceptibility of certain irAEs: Just determining what side effects patients have

experienced will not really lead to a meaningful analysis with similar information

available on the Opdivo and Keytruda sites themselves. Instead, I want to find

patterns in the data such as the percentage of patients that have experienced a

certain response and if different irAEs have constantly appeared in specific times of

treatment. What I am able to analyze greatly depends on the parameters of the data

itself.

6. Learn about the common Opdivo and Keytruda irAEs and compare and

contrast with my observations: I will utilize the FDA approval papers for Opdivo

and Keytruda to determine the major side effects of both drugs and see if the

patients used in my original work have experienced similar reactions. This analysis

will be a separate section of my final article.

7. Based on results from step two, determine if a statistical test could be

appropriately performed and if so, determine what type: Any major scientific

analysis needs a statistical backing to determine if observed data has statistical

significance. However, since my sample size is small, I need to examine the data first,

before knowing if a statistical test would be plausible. At the moment, the most

obvious statistical test to use is a 2-sample T-test— the same test I used in my

original work last year.

8. Research how to clinical study papers and begin the first draft of my article:

Format my article like the UpToDate article provided by Dr. Bhogaraju. My article

should be multiple sectioned and understandable to a common reader.

9. Proof-read my research paper and ask others to provide constructive

criticism on my work: Ask my mentor, English teacher, biology teacher, and three

classmates to read my work and give feedback.

10. Start part two of my original work by finding ten scientific resources to use to

find oncology news for my cancer website: Use sources from Scientific American

and links provided by the Sam Rhine’s genetic conference. Additionally, ask mentor

about what sources he reads to keep up with oncology news and subscribe to them.

11. Redesign my website to look professional and match the theme of my original

work: The website domain I own houses a site that I had not cleaned or adjusted the

theme of. I want to make my website an appealing minimalist color and feeling.

12. Update my website with links to the cancer research I find from numerous

oncology sources: Expand website by adding found research in tabs for easy

access.
 13. Distribute my website link to fellow students interested in oncology: Email

oncology source to both current ISM students studying cancer and prospective

future ISM students interested in oncology.

14. Present my research article and website on Final Presentation Night

Materials

● iPage website domain ($7.99 per year)

● Subscription to oncology websites, papers, organizations (Varies: some free)

● Research Portfolio Materials: presentation file, paper, tabs (Approximately: $20-

$30)

Total Cost: Approximately: $30-$40

Conclusion

While my original work has multiple parts and is certainly a cumbersome process,

the benefits arising from it will be worth the work. Like last year, this will be a long-term

project and will require a lot of dedication. Understanding the signal transduction

pathways of specific immune responses is difficult and based on heavy biology and

complex terminology. However, I know reading in depth about biology topics is something

that will be required of me in medical school and college in general, so my original work is

a great way to prepare for the future. Moreover, I know being a healthcare profession

requires dedication even higher than I mentioned above, so my project and ISM year, in

general, has been easing me into the commitments level of being a successful doctor.

Conducting this original work will allow me to witness the clinical side of research,

allowing me the full circle of cancer research. I have seen from the perspectives of both the

academic research and active doctor, and after this project, I am sure I will have an even
better grasp at which area of the cancer field I want to delve into. I hope that with my work

this year, I will be able to find a new perspective on cancer clinical data that will help the

scientific world. Of course, this is an ambitious idea, but the interesting thing about

medicine is that there is always something to be discovered. I hope to start my

contributions to the oncology field—no matter how small—with this year’s original work

project.

Calendar/ Timeline
March 9, 2018:
● Finalize initial research to begin actively working with patient data

● Schedule a mentor visit to determine with Dr. Bhogaraju if the data from forty-five

patients is sufficient in completing my original work

● Send a thank you card to Ms. Whitney Anderson for helping with my original work

March 16, 2018:

● Determine the irAEs experienced by the patients and the frequency of occurrences

● Note if there are any correlations among patient parameters and susceptibility of

certain irAEs

March 23, 2018:

● Learn about the common Opdivo and Keytruda irAEs and compare and contrast

with my observations

● Based on results from step two, determine if a statistical test could be appropriately

performed, and if so, determine what type

March 30, 2018:

● Research how to clinical study papers and begin the first draft of my article
April 6, 2018:

● Proof-read my research paper and ask others to provide constructive criticism on

my work

April 13, 2018:

● Start part two of my original work by finding ten scientific resources to use to find

oncology news for my cancer website

April 20, 2018:

● Redesign my website to look professional and match the theme of my original work

April 27, 2018:

● Update my website with links to the cancer research I find from numerous oncology

sources

● Add final touches to my projects

May 4, 2018:

● Distribute my website link to fellow students interested in oncology

● Present my research article and website on Final Presentation Night

Opdivo Common irAE Occurrence Frequencies
Initial Tumor Immunology Research