CAR T Cell Immunotherapy

Describe and review an important innovation within

your professional area or field of study/interest

CAR T-CELL Therapy

Name: Rahmasella Yolanda Sitepu 

ID Number: 001134367 

Class: EAP Advanced 

Lecturers: Karen Barnett and Susannah McCallum 

Due Date: 2/06/2020 (Final) 

Word Count: 1423 words

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Table of Contents

Introduction..............................................................................................................................................3

Detailed description of innovation.....................................................................................................3

Reasons for & source of development..............................................................................................7

Impacts of innovation............................................................................................................................9

Reviews of the innovation by experts.............................................................................................10

Conclusion and Personal Reflection...............................................................................................10

References.............................................................................................................................................11

Appendices............................................................................................................................................13

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Introduction

Cancer is a disease that results when there is the uncontrolled growth of abnormal cells

in the body (Cancer Treatment Centers of America 2019) (see image 1). Nowadays,

the increasing numbers of people that are diagnosed with cancer has become a major

concern, therefore finding alternative therapies for treating cancer that are safe and

effective has become one of the main goals for researchers around the world. One of

the alternative therapies for cancer is by immunotherapy. Immunotherapy is a treatment

that uses certain parts of a person’s immune system to fight cancer (Cancer Australia

2015).

Image 1: Cancer cell (Eldridge 2013)

This essay will discuss and provide a detailed description of CAR T-Cell

immunotherapy, the reason why they have developed the treatment, the person who

developed it, the impacts on medical area especially on cancer treatment, reviews from

the experts about this innovation and the personal reflections.

Detailed description of innovation

One of the new forms of immunotherapy for treating cancer is CAR T-Cell therapy. CAR

T-Cell therapy is a term for Chimeric Antigen Receptor T – Cell. CAR T-Cell therapy is a

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cancer treatment that uses specially engineered patient immune system from white

blood that is called T cells to fight cancer (Dana-Farber Cancer Institute 2014).

CARs (the receptor) are composed of three regions such as the ectodomain, the

transmembrane domain and the endodomain (see image 2). The ectodomain consists

of 3 components such as a signaling peptide, an antigen recognition region for

recognizing the cancer cells surface antigen and a spacer (see image 3). The antigen

recognition region in CAR is called a single chain variable fragment (scFV) (yellow part

see image 3), a type of protein known as fusion protein or chimeric protein.

Image 2: CARs cell structure (Zhang et al.

2017)

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Image 3: the ectodomain structures (Zhang et al. 2017)

Like other types of immunotherapy to treat a patient that has cancer, there are five

steps to make the CAR-T cell work (see image 4). The first stage is when the T cells

are collected from a patient via apheresis, a process using a machine that takes out the

needed parts like white blood cells including T cells and returns the unneeded parts of

the blood to the patient. Then, the T cells are sent to the lab. The second stage

happens in the lab or manufacturing facility where the T cells are genetically engineered

to find cancer killer cells by placing an inactive virus to insert the genes into the T cells

this produces special receptors that are called CARs on the surface of the T cells. After

that the modified T cells are multiplied until there are enough of the CAR-T cells. Then,

in the third stage the CAR-T cells are frozen and sent to the hospital where some of the

patients are being treated. At the hospital the CAR-T cells are defrosted and then

infused into the patient’s bloodstream after chemotherapy is given to make space and

allow the cells to multiply. Finally, in the fourth step the CAR-T cells are put back into

the patient’s bloodstream. And on the last steps the receptors will recognize and attack

the cancer cells that have the targeted antigen on their surface (see image 5). The
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CAR-T cells may eliminate all the cancer cells and may last in the body for some time to

help prevent the cancer cell from returning (LaRussaA 2015).

Image 4: Mechanisms of

CAR-T cell therapy (Cancer

Research UK 2018)

Image 5: Diagram of CAR-T

cell mechanism in the body

(Cancer Research UK 2018)

The field of immuno-oncology has developed as one of the great success stories of the

past decade, since the FDA approved CD19-CAR-T cells for treating acute

lymphoblastic leukemia in 2017 (see appendix A). There have now been more than

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100 clinical trials testing for CAR-T cells (June et al. 2018) (see graph 1). There are

also statistics that show the number of CAR-T cell therapy trials worldwide from 2007 to

2016 (see graph 2).

Graph 1: Regional disparities in

studies of CAR-T cell therapies

(Cary 2018).

Graph 2: Number of CAR cell

therapy trials worldwide 2007

– 2016 (Mikulic 2017)

Reasons for & source of development

From 1989 – 1993 (See appendix A), Israeli immunologists from the department of

Chemical Immunology of Weizman Institute of Science in Rehovot Israel, named Zelig

Eshhar and Gideon Gross developed the first engineered T-cell with chimeric molecule

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(Styczyński 2020). The first generation of CAR was developed in 1989 and used CD3z

as the only stimulation molecule to activate T cells, which in turn revealed defects in

weak proliferation abilities, poor anti-tumor effects, and the survival of short T cells.

However, the first-generation CARs were not clinically effective. Over the next thirty

years, CARs have become more immunologically and technologically modern and

sophisticated than the first, second, third and currently fourth generation (see image 6),

depending on their composition.

In 2003 (See appendix A), the second-generation of CARs were developed with an

improvement on the anti-tumor activity of T cells. The second-generations CARs have

included an additional intracellular co-stimulatory domain which typically from CD28 or

CD4-1BB that improves overall survival, proliferation and persistence of activated CAR-

T cells (King 2018) (see image 6).

In 2014 (See appendix A), the third generation of CARs were developed with an

improvement of effector functions and in vivo persistence. In the third generation of

CARs the CD3z are replaced by a stimulatory killer immunoglobulin-like receptor (KIR)

KIR2DS2 and DNAX-activating protein of 12 kDA (DAP12) to enhance the proliferation

and function of the CAR-T cells which has a purpose of efficiently destroying the

immunotherapy-resistant solid tumors (CreativeBiomart 2018) (see image 6).

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Image 6: Generation of T-cell (Creative Biomart 2018)

In 2015 (see Appendix A), the fourth generations of CARs were developed and the so-

called TRUCKs (T cell Redirected for Universal Cytokine Killing). The fourth generation

looks like the 2nd generation, however this newest generation has an addition of gene

cassettes for cytokines or co-stimulatory ligands that can be controlled through the

antigen that is binding to the CARs (King 2018) (see image 6).

Impacts of innovation

The FDA approved several treatments to cure leukemia and lymphoma using the CAR-

T cell therapy. These treatments are Tisagenlecleucel (Kymriah), Axicabtagene

ciloleucel (Yescarta) and Tocilizumab (Actemra). Statistics show over 80 percent of

patients who receive Yescarta treatment in clinical trials have experienced either no

more signs of cancer or partial response which means there was some reduction on the

number of cancer cells in the body (Cleveland Clinic 2018). There are also some side

effects for patients that have CAR-T cell treatment like when cytokine is released which

creates some syndromes that like flu, shortness of breath, low blood pressure and fast

heart rate. There are also some neurologic effects like brain disease, malfunction,

confusion, aphasia (difficulties in understanding or speaking) (Cleveland Clinic 2018).

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Reviews of the innovation by experts

A number of CAR-T cell therapies are already available to some of the hospital around

the world, but these are expensive. According to professor of medicine at Oregon

Health & Science University’s Knight Cancer Institute named Richard T. Mazriaz,MD the

total cost of care that hospital charged with CAR-T cell therapy treatment like

Tisagenlecleucel (Kymriah) is $1.5 million per cancer patients and these are includes

the cost of drug, administration and often inpatient care for toxic side-effects (Anon,

2019). Therefore, one solution that might be stated by an expert is to reduce the cost of

allogenic CAR T treatment by supplying T lymphocytes from healthy individuals that can

be easily used when a patient needs them, rather than genetically modifying each

patient's T cells individually.

Conclusion and Personal Reflection

In conclusion, CAR-T-Cell therapy is considered become highly innovative, effective

and being the biggest breakthrough in cancer treatment for years. However, there are

several side effects for patients that have this treatment like lowering the blood pressure

and fevers in the following days after the treatment is given to a patient. The other

serious problems for the patient if the experts can not find any solution to tackle the

problem that the CAR-T cells can kill off some of the good B cells that help fight germs,

so in some way the patient may be at risk of getting infections. So, in my opinion after

more testing and development of new technology is needed help the CAR-T cell therapy

become more advanced. The CAR-T cell therapy could become one of the most

promising treatments for curing cancer and also could increase the number of people

who are survive.

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References
Anon, 2019. CAR T-cell therapy total cost can exceed $1.5 million per treatment.
Healio.com, viewed 17 Jun. 2020 <https://www.healio.com/news/hematology-
oncology/20190529/car-tcell-therapy-total-cost-can-exceed-15-million-per-treatment>.
Cancer Australia 2015, Immunotherapy, canceraustralia.gov.au, viewed 2 June 2020,
<https://canceraustralia.gov.au/affected-cancer/treatment/immunotherapy>.
Cancer Research UK 2018, CAR T-cell therapy | Immunotherapy | Cancer Research
UK, Cancerresearchuk.org, viewed 2 June 2020,
<https://www.cancerresearchuk.org/about-cancer/cancer-in-
general/treatment/immunotherapy/types/CAR-T-cell-therapy>.
Cancer Treatment Centers of America 2019, What is cancer? www.cancercenter.com,
viewed 2 June 2020, <https://www.cancercenter.com/what-is-cancer>.
Cary, N 2018, Regional disparities in studies of CAR T cell therapies., in Science (ed.),
Science, vol. 359, no. 6382, pp. 1361–1365, viewed 2 June 2020,
<https://science.sciencemag.org/content/359/6382/1361>.
Cleveland Clinic 2018, CAR T-Cell Therapy Risks / Benefits, Cleveland Clinic, viewed 2
June 2020, <https://my.clevelandclinic.org/health/treatments/17726-car-t-cell-
therapy/risks--benefits#:~:text=The%20most%20common%20side%20effects>.
Creative Biomart 2018, Structure and Generations of CAR-T cell,
www.creativebiomart.net, viewed 2 June 2020,
<https://www.creativebiomart.net/Targets-of-CAR-T-Cell-Therapy.htm>.
CreativeBiomart 2018, Targets of CAR-T Cell Therapy - Creative BioMart,
www.creativebiomart.net, viewed 2 June 2020,
<https://www.creativebiomart.net/Targets-of-CAR-T-Cell-Therapy.htm>.
Dana-Farber Cancer Institute 2014, Frequently Asked Questions About CAR T-Cell
Therapy - Dana-Farber Cancer Institute | Boston, MA, Dana-farber.org, viewed 2 June
2020, <https://www.dana-farber.org/cellular-therapies-program/car-t-cell-therapy/faq-
about-car-t-cell-therapy/>.
Eldridge, L 2013, Cancer Cells vs. Normal Cells: How Are They Different?, Verywell
Health, Verywellhealth, viewed 2 June 2020, <https://www.verywellhealth.com/cancer-
cells-vs-normal-cells-2248794>.
June, CH, O’Connor, RS, Kawalekar, OU, Ghassemi, S & Milone, MC 2018, ‘CAR T cell
immunotherapy for human cancer’, Science, vol. 359, no. 6382, pp. 1361–1365, viewed
2 June 2020, <https://science.sciencemag.org/content/359/6382/1361>.
King, D 2018, FDA Approves First CAR T-Cell Therapy – The evolution of CAR T-Cell
Therapy, Cell Culture Dish, Cell Culture Dish, viewed 2 June 2020,
<https://cellculturedish.com/fda-approves-first-car-t-cell-therapy-the-evolution-of-car-t-
cell-therapy/>.

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LaRussaA 2015, Chimeric Antigen Receptor (CAR) T-Cell Therapy | Leukemia and
Lymphoma Society, Lls.org, viewed 2 June 2020, <https://www.lls.org/treatment/types-
of-treatment/immunotherapy/chimeric-antigen-receptor-car-t-cell-therapy>.
Mikulic, M 2017, CAR cell therapy trials globally 2007-2016, Statista, viewed 2 June
2020, <https://www.statista.com/statistics/687310/car-cell-therapy-trials-worldwide-
number/>.
Mohanty, R, Chowdhury, C, Arega, S, Sen, P, Ganguly, P & Ganguly, N 2019, "CAR T
cell therapy: A new era for cancer treatment (Review)", in, Oncology Reports, vol. 42,
no. 6, pp. 2183-2195, viewed 18 June 2020,
<https://search.proquest.com/docview/2317551568?rfr_id=info%3Axri%2Fsid
%3Aprimo>.
Styczyński, J 2020, ‘A brief history of CAR-T cells: from laboratory to the bedside’, Acta
Haematologica Polonica, vol. 51, no. 1, pp. 2–5, viewed 2 June 2020,
<https://content.sciendo.com/view/journals/ahp/51/1/article-p2.xml?language=en#j_ahp-
2020-0002_ref_005_w2aab3b8b3b1b7b1ab2b2b5Aa>.
Zhang, C, Liu, J, Zhong, J & Zhang, X 2017, "Engineering CAR-T cells", in , Biomarker
Research, vol. 5, no. 1, viewed 17 June 2020,
<https://biomarkerres.biomedcentral.com/articles/10.1186/s40364-017-0102-y#citeas>.

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Appendices

Appendix A: History of development of CAR effector cells (Styczyński 2020)

Year Achievement
1989 Generation of effector T cells expressing chimeric T-cell receptor
1993 First-generation CAR-T cells, not clinically effective
2002 First effective CAR-T cells against prostate cancer antigen in the laboratory
Second-generation CARs: CD19-directed CAR-T cells can kill leukemia cells in
2003
mouse
2009 CD19 CAR-T cells used in relapsed/refractory leukemia
2011 CD19 CAR-T cells in patients with chronic lymphocytic leukemia
2013 CD19 CAR-T cells in paediatric acute lymphoblastic leukemia
Science magazine announced cancer immunotherapy as “Breakthrough of the
2013
Year”
Third-generation CAR-T cells: inducible caspase-9 suicide gene system as a
2014
“safety switch” to limit on-target, off-tumour toxicities
Fourth-generation CARs, the so-called TRUCKs (CAR redirected T cells that

2015 deliver a transgenic product to the targeted tumour tissue) or armoured CARs,

which produce other molecules built and being tested for ovarian cancer
2015 Concept of CAR-NK cells
Clustered regularly interspaced short palindromic repeats (CRISPR) used to
2017
optimize CAR placement in T cells
FDA approves CD19-CAR-T cells for relapsed/refractory acute lymphoblastic
2017
leukemia in children and young adults
2017 FDA approves CD19-CAR-T cells for relapsed/refractory DLBCL in adults
EMA approves CD19-CAR-T cells for relapsed/refractory acute lymphoblastic
2018
leukemia in children and young adults and for relapsed/refractory DLBCL in adults
Dual CD19/CD22 CAR-T cells in acute lymphoblastic leukemia in children and
2019
adults

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