REVIEW OF CAR T-CELL THERAPY AND ITS USE IN THE TREATMENT OF SOLID 
TUMOR CANCERS 

By 

Bryce Johnson 

A THESIS 

Submitted to 
Michigan State University 
in partial fulfillment of the requirements 
for the degree of 

Basic Medical Science—Master of Science 

2024 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ABSTRACT 

CAR T-cell immunotherapy has been rapidly developing over the last 2 decades. The 

expanding list of cancer targets provides more and more treatment opportunities. The purpose of 

this research review is to discuss CAR T-cell immunotherapy, to compare and contrast this 

therapy to the gold standards of cancer treatment, and to examine its developing use for solid 

tumor cancers. 

Targeted immunotherapies, such as CAR T-cells, are a more recent addition to the 

treatment options for solid tumor cancers. While initially developed for use with hematologic 

malignancies, CAR T-cells have now successfully been used to treat a variety of solid tumor 

cancers (National Cancer Institute, 2022). The use of CAR T-cell immunotherapy for solid 

tumors is promising, with about 30 antigens being targeted in ongoing clinical trials (Newick et 

al., 2016). The current opportunities for treatment include lung cancer, kidney cancer, bone 

cancer, breast cancer, prostate cancer, and glioblastoma (Guzman et al., 2023). 

The use of CAR T-cell immunotherapy for solid tumor cancers faces obstacles such as 

cell trafficking restrictions into the tumor site, a hostile tumor microenvironment, antigen 

heterogeneity, CAR T-cell exhaustion, and potential severe toxicities that can hamper clinical 

efficacy. With new and ongoing research of potential antigen targets and the development of 

counter strategies, such as combination therapies and additional modification of the CAR T-cells, 

being tested, there still significant potential therapeutic efficacy for the use of CAR T-cell 

immunotherapy for solid tumor cancers. 

Keywords: CAR T-cells, immunotherapy, solid tumor

 
 
 
TABLE OF CONTENTS 

I. 

II. 

III. 

INTRODUCTION ...............................................................................................................1 

USE OF CAR T-CELLS FOR SOLID TUMORS ..............................................................4 

CURRENT LIMITATIONS AND POTENTIAL ADVANCEMENTS OF CAR T-
CELLS ...............................................................................................................................14 

IV.       CONCLUSION..................................................................................................................17 

BIBLIOGRAPHY ..........................................................................................................................18

iii 

 
 
I. 

 INTRODUCTION 

Cancer is one of medicine’s most difficult problems. There are about 1.9 million new 

cases diagnosed each year in the United States, and about 600,000 yearly cancer related deaths 

(American Cancer Society, 2024), placing cancer as the second leading cause of death in the US. 

The economic burden of cancer treatment in the US was $21.09 billion in 2019, and the 

American Cancer Society estimates that it could balloon to as much as $246.6 billion by 2030 

(National Cancer Institute, 2021). While there are many pharmacological and surgical solutions 

being developed and refined all the time, each treatment type comes with its own set of 

drawbacks, which perpetually leaves the door open for further advancements. 

Cancer is characterized by abnormal, uncontrolled cell division. There are many different 

types of cancers borne of a wide variety of different cell types, with many ways of classifying 

and grouping the cancer types. Largely, cancers can be separated into solid tumors and non-solid 

(liquid) tumors. One example of liquid tumors are the leukemias, which are cancers of the body’s 

blood forming tissues and develop in blood, bone marrow, and lymph. Solid tumors make up 

90% of adult cancers and 40% of childhood cancers (American Cancer Society, 2024). Solid 

tumors are made up of abnormal cells of a single type that communicate through tight and gap 

junctions. Solid tumors form a “mass” as the cells multiply, and usually contain no fluid, pus, air, 

or other substances. While the treatment of solid tumors and liquid tumors have a lot of overlap, 

there are also many differences in the needs and availability of treatments for each. Solid tumor 

cancers include sarcomas, carcinomas, and lymphomas. 

For years, the phrase “cure for cancer” has been synonymous with an elusive scientific 

breakthrough. While there is no so-called “cure” for cancer just yet, there are many effective 

options for the treatment of cancer available to medical professionals. Surgery, chemotherapy, 

1 

 
 
and radiation therapy are the most commonly used treatments in the US (American Cancer 

Society, 2024) and have been successfully used to treat cancer since the early 1900’s. More 

recently, targeted therapies have joined the other mainstay treatments and become foundational 

to the way that cancer is treated (National Cancer Institute, 2022). 

In order to treat cancer, it must first be defined and its mechanism understood. “The 

hallmarks of cancer” are an organizing principle that was developed to help streamline the 

complex nature of cancer so that it might be better understood. The hallmarks describe eight 

“capabilities” of cancer, and two “enabling capabilities”. These hallmarks describe what cancer 

is able to do, and must do, in order to effectively replicate, evade our bodies defenses, and invade 

tissue (Hanahan & Weinberg, 2011). 

These hallmarks include the eight capabilities: 

•  Self-sufficient growth signals 

• 

Insensitivity to anti-growth signals 

•  Evading apoptosis 

•  Limitless replicative potential 

•  Sustained angiogenesis 

•  Tissue invasion and metastasis 

•  Deregulated metabolism 

•  Evading the immune system 

And the two enabling capabilities are: 

•  Genome instability 

• 

Inflammation 

2 

 
 
The last two capabilities, as well as the two enabling characteristics, are a more recent 

addition to the hallmarks of cancer, having been proposed in 2011 to be added with the original 6 

that were proposed in 2000 (Hanahan & Weinberg, 2011). 

Being able to accomplish the phenotypes detailed in the hallmarks makes cancer cells 

virtually immortal, and sometimes beyond the natural healing abilities of which our bodies are 

capable. This transformation makes medical intervention a necessity to eliminate cancer. The 

hallmarks can work as targets for treatments, as the disruption of one or more of them can stop or 

slow cancer progression. 

Added to the defining qualities of a cancer was its ability to evade the immune system. 

When functioning normally, the immune system detects and eliminates abnormal cells, which 

prevents or reduces the growth of many cancers. For example, immune cells called tumor-

infiltrating lymphocytes (TILs) are oftentimes found in and around tumors (Yang et al., 2022). 

The secreted substances from these cells signal to the body that the immune system is responding 

properly to the tumor. Under normal conditions, TILs are lymphocytes that migrate to tumors 

and infiltrate them. TILs recognize tumor specific antigens, and use either direct or indirect 

cytotoxic activity to attack the tumor. TILs are constantly patrolling the body for tumors, and 

don’t need to be directed toward the tumors to attack (Yang et al., 2022). Patients that have 

tumors containing TILs typically have better outcomes than those that do not (Yang et al., 2022). 

Current available immunotherapies include immune checkpoint inhibitors, monoclonal 

antibodies directed at tumor cells, immune system modulators, and adoptive cell transfer. TILs 

are an example of adoptive cell transfer, which also includes chimeric antigen receptor (CAR) T-

cell therapy. While TILs will attack tumors on their own, CAR T-cells are genetically modified 

to seek out specific tumors based on their antigens (Yang et al., 2022). 

3 

 
 
II. 

 USE OF CAR T-CELLS FOR SOLID TUMORS 

A. 

THE PROCESS OF CAR T-CELL IMMUNOTHERAPY 

As stated, CAR T-cell therapy is classified as immunotherapy. Immunotherapies aim to 

either trigger, enhance, or block the immune response in order to achieve their medicinal goals. 

CAR T-cells are in the grouping of “activating” immunotherapies, as such they are designed to 

trigger mechanisms already used by our immune system and aim them at a cancer. Our bodies’ 

immune systems are made up of white blood cells and organs and tissues of the lymph system; 

these built in systems are some of the best disease destroying mechanisms known to humankind, 

and immunotherapy was created to take advantage of this powerful system. 

Under normal conditions, blood cells mature from stem cells, and then develop into either 

a myeloid or lymphoid precursor cell. The myeloid cells become the red blood cells and 

platelets, which are critical for the bodies’ oxygen delivery system and wound repair systems. 

The myeloid stem cells can also develop into granulocytes and macrophages, which are the white 

blood cells (WBCs) that are active in the innate branch of the immune system. These WBCs will 

respond generally to defend the body against foreign invaders during bacterial, viral or parasitic 

infections. Lymphoid stem cells are the other maturation branch from blood stem cells; theu 

become lymphocytes, which then develop into either B lymphocytes or T lymphocytes. These 

cells are active in adaptive immunity, which adapts to fight specific foreign invaders once they 

have come in contact with them. B lymphocytes are responsible for humoral immunity, which 

uses secreted antibodies, complement proteins, and certain antimicrobial peptides to protect the 

body against diseases. T-lymphocytes (T-cells) are responsible for cell mediated immunity. T-

cells can develop into a number of different subtypes, the relevant subtypes being helper T-cells, 

cytotoxic T-cells, or natural killer cells. In cell-mediated immunity, a macrophage or natural 

4 

 
 
killer cell, which are both activated to kill intracellular pathogens, will activate a helper T-cell to 

replicate by presenting it with an antigen from their ingested pathogens. Helper T-cells will 

replicate the signal to tell the cytotoxic T-cells to proliferate and kill foreign invaders. The 

molecules that helper T-cells use to signal the cytotoxic T-cells are called cytokines, which are 

small proteins that act as chemical messengers between cells. Cytokines carry signals that control 

the immune system and other cells in the body. 

CAR T-cell therapy works by increasing the cancer fighting capabilities of T-cells. The 

immune system monitors the body for foreign cells, which is how it views cancerous cells, by 

tracking proteins on the surface of the invading cells called antigens. The immune system relies 

on T-cells to track and kill foreign entities, including cancers. 

T-cells, like all cells, have proteins on their surface called receptors. When these 

receptors sense antigens, they signal to the T- cell what types of cells or particles are present in 

the body. When these receptors sense foreign antigens, the T-cells attempt to catch and block the 

foreign substances. More than that, T-cells can kill the foreign substances and/or the cells that 

harbor the foreign substances. But antigens have their own form of protection because they can 

disguise themselves to hide from T-cells. CAR T-cell therapy ensures your T-cells aren’t fooled 

by antigens in disguise. 

As early as the 1990’s, researchers demonstrated how the introduction of donor T-cell 

precursor cells into a patient with cancer can induce remission (Sun et al., 2024). In 1997 

researchers did this with patients with chronic myeloid leukemia using a process called 

allogeneic stem cell transplantation (Kolb & Holler, 1997). Allogeneic stem cell transplantation 

involves extracting healthy stem cells from a donor's bone marrow surgically with a needle and 

then introducing the donated cells to the patient’s body. 

5 

 
 
CAR T-cells are made by modifying a patient’s existing T-cells ex vivo so that they 

express something called a chimeric antigen receptor (CAR). These CAR T-cells are essentially 

turned into a hybrid of B and T-cells, with a T-cell activating signal portion and an antibody-like 

antigen recognizing portion (Sun et al., 2024). The antibody portion of the CAR T-cell consists 

of a single-chain variable fragment derived from heavy and light chains. This redirects 

specificity and allows the T-cells to recognize the antigens present in the tumor cells without use 

of major histone compatibility complex proteins (Sun et al., 2024). 

Figure 1. Created with biorender.com 

The majority of advancements in the structure of CAR T-cells have been in modifying 

their intracellular T-cell activating portion. First generation CAR T-cells only included a CD3 

domain, while second generation and beyond have added costimulatory molecule (CM) domains 

in order to improve activation and enhance effectiveness. These advancements have led to CAR 

T-cells being known as a “living drug” (Jackson et al., 2016). In its early days, CAR T-cells were 

used primarily on liquid tumors (Jackson et al., 2016). The improvements in the third and fourth 

6 

 
 
 
 
generations of the treatment has expanded the possibilities of use for many solid tumors as well, 

with the use of additional costimulatory domains and genes for cytokine secretion that have 

allowed for a larger variety of target antigens (Rohit et al., 2021). 

Below is a table to summarize the 5 generations of CAR T-cells. 

Table 1. A summary of CAR T-cell generations. 

Features  

Limitations 

1st 
Generation 

•  one signaling domain 
• 

capable of T-cell activation only 

2nd 
Generation 

3rd 
Generation 

4th 
Generation 

5th 
Generation 

• 

Inadequate T-cell 
proliferation 
•  Cytokine release 
•  T-cell persistence 
•  Antitumor activity 

•  T-Cell persistence 
•  Relapse 

•  Higher incidence of severe 
side effects (e.g., CRS and 
faster T-cell exhaustion) 

•  Provides two signals via CD3ζ and 

• 

CM 
Improved T-cell activation, 
proliferation, and persistence over 
gen 1 

•  Multiple signaling via CD3ζ and 2 

• 

CMs 
Improved safety profiles, 
proliferation, perseverance, and 
anti-tumor functions 

•  Primary CD3ζ, costimulatory 

•  Poor cancer-killing 

signals 

•  Expression of transgenic proteins 
•  Potentiates T-cell expansion, 
persistence, and anti-tumor 
capacity by overcoming tumor 
antigen loss by cytokine activation 
at the tumor site and modulating 
the tumor milieu 
•  Reduced toxicity 

• 

• 

Improved T-cell activation, 
proliferation, solid tumor 
infiltration, and persistence by 
cytokine-inducing JAK/STAT 
signaling 
Improved safety profile 

7 

potential in solid tumors 

•  Side effects such as on-

target off-tumor activation 
of TRUCK T-cells and 
release of the transgenic 
cytokine in healthy tissues 
•  Double modification of T-

cells 

•  Limitations infiltrating and 
trafficking into solid tumors 
when compared to blood 
cancers 

•  Associated with some side 

effects 

 
 
 
Table 1 (cont’d) 

5th 
Generation 
(cont’d) 

•  Wider therapeutic window 
•  Creates a more favorable tumor 
milieu and reestablishes the 
immune system after infusion 

(Asmamaw Dejenie et al., 2022) 

The first step in preparing CAR T-cell treatment is collecting T-cells from the patient. 

These cells from the patient are called “autologous T-cells”. The patient undergoes apheresis, a 

process where blood is removed from the body and passed through a machine that separates the 

blood cells and blood products from the blood plasma. Apheresis is followed by leukapheresis, 

which allows for the further filtering of the blood cells according to size. Leukapheresis allows 

for the separation of the white blood cells (leukocytes) and the isolation of the T lymphocytes 

that are to be used in the treatment. Unused portions of the blood are then reintroduced into the 

patient (Wang et al., 2023). 

The separated T-cells are then sent to a lab for genetic engineering. Genetic engineering 

of the T-cells is accomplished by inserting genes by way of an inactive virus/non-virus vector, 

which will produce the CARs on the surface of the patient’s T-cells. The modified T-cells are 

then allowed to grow for 2-3 weeks after which they are frozen (Wang et al., 2023). Lastly, the 

modified T-cells are injected back into the patient via a single infusion. Patients receive 

chemotherapy before this last step to deplete their own lymphocytes. This treatment reduces the 

population of the less helpful native population of T-cells and gives the newly introduced CAR 

T-cells room to expand (Subklewe et al., 2019). 

Another area of progress with CAR T-cell treatment is the use of “allogeneic T-cells”. In 

this process, T-cells from a donor are used instead of the patient’s own. This overcomes some of 

the disadvantages of autologous T-cells in regards to the time of production, the cost, and 

8 

 
 
 
manufacturing delays (Martínez Bedoya et al., 2021). Another benefit of donor T-cells is that it 

alleviates dependance on the patient’s T-cells that may have reduced function or supply due to 

previous cancer treatments (Martínez Bedoya et al., 2021). 

B. 

POTENTIAL BENEFITS AND NEGATIVES OF CAR T-CELL 

IMMUNOTHERAPY 

Unlike most other forms of cancer treatment, CAR T-cells are customized to the 

individual patient. The cancer is being fought by the patient's own T-cells, which are modified to 

attack the antigens that are specific to the patient’s cancer tumor. The patient’s body also makes 

more of the CAR T-cells because the CAR T-cells replicate inside the patient after initial 

injection via clonal expansion. 

The leading benefits of CAR T-cell immunotherapies are the short treatment time that is 

required to complete the therapy course. CAR T-cell treatment also boasts a more rapid recovery 

than traditional cancer treatments, and scores higher in long term remission, with a better 

reported quality of life (NIH, 2022). 

In one trial where CAR T-cells were being directed towards HER2-expressing 

glioblastoma (GBM) tumors, 7 out of 16 patients had stabilized their disease for up to 29 months 

(Daei Sorkhabi et al., 2023). The average survival time was 24.5 months from time of diagnosis. 

Using traditional glioblastoma treatments (surgery, followed by radiation therapy with or without 

chemo), the average survival of a patient is 12-15 months (Marra et al., 2019). This is a very 

significant increase in the lifespan of GBM patients, who’s median survival is under 12 months 

(Mohammed et al., 2022). This shows how monumental this treatment could be for the treatment 

of certain solid tumor cancers if some of the current treatment barriers can be overcome. 

9 

 
 
At the moment, CAR T-cell therapy is primarily being used only after a patient has failed 

several lines of more traditional treatments, but there is a push to use CAR T-cells as first line in 

some cases (NIH, 2022). One study compared 3 trials using CAR T-cells after patients received a 

single treatment of chemotherapy for non-Hodgkin lymphoma, versus patients receiving only the 

standard treatment approach. In two of the three trials, patients that had received the CAR T-cell 

therapy lived longer without progression of the disease than patients who underwent the standard 

treatment (NIH, 2022). One of those trials showed patients given CAR T-cell treatment for large 

B-cell lymphoma had a median event-free survival of 10.1 months versus only 2.3 months with 

standard of care treatment (Kamdar et al., 2022). 

While the side effects associated with CAR T-cell immunotherapy are typically less 

severe than those of conventional cancer treatments like surgical excision, chemotherapy, and 

radiotherapy, that does not mean they are nonexistent (NIH, 2022). One of the most concerning 

side effects is the cytokine release syndrome (CRS), also known as “cytokine storm”. When 

immune cells attack an infection, they release cytokines. Cytokines are small proteins that are 

important for cell signaling. When too many cytokines are released, they can wreak havoc on the 

body leading to fever, chills, hypotension, tachycardia, breathing difficulty and lowered oxygen. 

If a patient is suspected of having CRS, vitals will need to be closely monitored, including 

ferritin levels and C-reactive protein. They may need to be given oxygen for hypoxia and fluid 

for hypotension. 

On-target, off-target toxicity is also a side effect experienced by some patients who take 

CAR T-cell therapy. On-target, off-target toxicity is when antigens targeted by the CAR T-cells 

are also expressed on the nearby healthy cells. This side effect can be life threatening when these 

healthy cells are essential, such as in the heart, lungs, or liver. When using allogeneic CAR T-

10 

 
 
cells, a disease known as graft vs. host disease (GVHD) may be an issue, where the immune 

system attacks foreign donated tissues and cells. Anaphylaxis is another potential side effect, as 

well as tumor lysis syndrome (fragments of destroyed tumor in the bloodstream).  

Pricing can also be an issue when considering whether CAR T-cell therapy is the right fit 

for a patient. Experts estimate that CAR T-cell therapy can cost between $500,000 and 

$1,000,000 (Choi et al., 2022). For comparison, the average monthly cost for chemo is about 

$1,000 to $12,000 depending on the drugs, and about $48,000 total (Choi et al., 2022). Private 

insurance may or may not pay for CAR T-cell therapy, and Medicaid only covers it depending 

on the state. Even if insurance does cover it, that does not mean no out of pocket expenses. 

C. 

CAR T-CELL IMMUNOTHERAPY COMPARED TO ALTERNATIVES 

While the mainstay gold standards for the treatment of solid cell cancers can result in 

successful outcomes, every available therapy has drawbacks. During modern radiation therapy, 

doctors are able to create a 3D model of the tumor and surrounding area in order to target the 

cancer and spare the normal tissue. Radiation therapy is able to cause the death of a large portion 

of the cancer cells within a tumor. This treatment is relatively safe and is useful for shrinking 

tumors before surgical excision, or possibly even eradicating smaller tumors (Debela et al., 

2021). Radiation therapy kills cancer cells or slows their growth at high doses by damaging the 

DNA beyond repair. The radiation exposure will directly kill the cancer cells or weaken them, 

which stimulates the immune system and allows the cancer cells to then be broken down and 

cleared by the cells of the immune system (Debela et al., 2021) 

While peripheral organ preservation is significant with radiation therapy, close proximity 

of a tumor to surrounding tissues can cause them to be damaged by the treatment. Radiation 

therapy can kill healthy cells that are not accurately represented in the 3D model, potentially 

11 

 
 
disrupting wound healing. Radiation therapy can also be an inconvenience to the patient as the 

treatment can be delivered daily, up to 5 times per week, and up to 2 months (Debela et al., 

2021). 

Chemotherapy is typically considered the treatment of cancers using chemical 

substances, but today can involve the use of small molecules and biologics. The benefits of 

chemotherapy include its ability to act systemically. This systemic activity allows for the 

treatment of cancers throughout the whole body, including cancers that are bloodborne or have 

spread to multiple areas. Chemotherapy can be used alongside radiation therapy, which can boost 

the effects beyond what either treatment would do on their own. Some specific patient tailoring 

can be done, as there are more than a hundred chemo drugs available for patients and doctors to 

choose from (NCI, 2022). Chemotherapy can also be a good option if a partial or total organ 

removal would negatively impact the patient’s life, as there is a possibility it might eliminate or 

limit the need for surgical resection. An example of this would be using chemotherapy to treat a 

woman’s uterine cancer instead of treating the cancer with a complete hysterectomy, as she may 

not have completed her family and still wants to carry a child. 

For nearly as long as cancer treatment has existed, the first line treatment for most solid 

tumors was surgical resection. The surgery process involves patients being taken to an operating 

room, being put under anesthesia, and the tumor being removed by a surgeon. This is either a 

complete removal of the solid tumor, or a partial removal, called debulking, in cases where total 

excision cannot be achieved. There are many benefits to this treatment option, including 

removing a large volume of the tumor that relieves mass effect, removal of all cancer cells in a 

small area, and the treatment may take as little as a single session while the patient is 

unconscious. Another benefit of surgery is the ability to send the removed tissue sample to a 

12 

 
 
pathologist, who is then able to check the margins of the sample to confirm whether or not all the 

cancer cells were removed. Looking at the top 10 solid tumor cancers in the US, only about 

8.85% of surgeries return positive margins results, meaning there was still cancer found in the 

periphery of the sample and therefore likely still present in the patient (Orosco et al., 2018). 

The drawbacks of surgical treatment are the inability to kill microscopically, some 

cancerous cells may be left behind on the margins, some patients cannot tolerate anesthesia, 

some damage to nearby structures may occur, surgical complications that are not site specific, 

inability to remove cancer from other parts of the body (metastasis), and removal of organs that 

may decrease the patient’s quality of life. 

13 

 
 
 
 
III. 

CURRENT LIMITATIONS AND POTENTIAL ADVANCEMENTS OF CAR T-

CELLS 

A. 

SOME DRAWBACKS TO CAR T-CELLS 

As of today, one of the biggest hurdles for the use of CAR T-cells against solid tumor 

cancers is finding the right antigenic target. The issue here is tumor heterogeneity, which means 

all the cells in the tumor might not have the antigen that the CAR T-cells are programmed to 

attack. While research in this area is ongoing, there has still been difficulty in finding antigens 

that target the unwanted cancer cells but leave the healthy cells unharmed. 

The surrounding environment poses a unique challenge for treating solid tumors. On a 

larger scale, physical barriers can block the CAR T-cells from reaching their intended targets. A 

major example of a physical barrier that can block CAR T-cells is the dysregulated tumor 

vasculature and dense fibrogenic extracellular matrix (ECM) (Kankeu Fonkoua et al., 2022). On 

a micro scale, immune-suppressing molecules that the cancer cells secrete can damage the CAR 

T-cells and render them useless. Immunosuppressive cytokines (interleukin-10, IL-4, and 

transforming growth factor β), tumor-associated macrophages, and regulatory T-cells hinder 

effective antitumor function of CAR T-cells (Kankeu Fonkoua et al., 2022). Competing for 

metabolic fuels (glucose and O2) can also hinder CAR T-cell function (Kankeu Fonkoua et al., 

2022). 

While the ability for “personalization” is one of the benefits of CAR T-cell therapies, a 

problem arises in this regard when it comes to solid tumors. Solid tumors can vary quite a bit on 

the molecular level for each patient, and sometimes even in the same patient. This can further 

hinder the process of finding a suitable target antigen, as there may be little to no suitable target 

14 

 
 
antigens on some tumor cells. If there are no suitable antigens the CAR T-cells cannot do their 

job as intended. 

B. 

LOOKING TO THE FUTURE 

CAR T-cells have many areas of development that will make up the next generation of 

CAR T-cells. Once these features are able to be implemented, they will overcome some of the 

barriers to the use of CAR T-cells for solid tumor cancers, as well overall improving their 

performance as a treatment. 

Overcoming CAR T-cell toxicity is a high priority for the next generation of CAR T-

cells, as safety is paramount when developing new medicines. The majority of CAR T-cell 

therapies are currently autologous small-scale treatments for patients that suffer from B-cell 

malignancies–liquid tumor cancers. One of the reasons CAR T-cell therapies are not used more 

for solid tumor cancers is due to the safety concerns about the potential development of a GVHD 

in allogeneic therapies, and therefore allogeneic therapies have been less effective than 

autologous ones. One way this problem is being addressed is through the use of something called 

a suicide gene switch. 

Suicide genes are genetically encoded elements that are integrated into CAR T-cells to 

allow for the elimination of the introduced T-cells in cases where the patient experiences 

toxicities. They are activated by the introduction of a pharmaceutical agent that triggers the 

inserted genes to kill the CAR T-cells with up to 90% efficiency (Moghanloo et al., 2021). A 

drawback to this process is expense. 

Bispecific T-cell engagers are another genetically encoded switch that can be added to 

CAR T-cells. These can allow for the switching of antigenic targets with already inserted CAR 

15 

 
 
T-cells. This will help overcome the problem of tumor heterogeneity when it comes to using this 

treatment for solid tumor cancers (Moghanloo et al., 2021). 

Combinational target-antigens are another method being used to overcome tumor 

heterogeneity. With this addition, once the CAR T-cells have been bound to one antigen they 

will then activate to bind to an additional target antigen; binding to both antigens is necessary for 

the modified T-cells to have full effect (Moghanloo et al., 2021). 

16 

 
 
 
 
IV. 

 CONCLUSION 

CAR T-cell immunotherapy has its place in the current line-up of solid tumor cancer 

treatments, with its own set of benefits and drawbacks. The “living drug” has immense potential 

when it comes to the treatment of solid tumor cancers. The benefits that CAR T-cell 

immunotherapy has brought to hematological malignancy, such as its customizability, 

convenience, and adaptability would be a welcome addition to the treatment of solid tumor 

cancers. And while there is great progress that has been made, and many promising trials and 

advancements on the horizon, there are still many hurdles that must be overcome for using CAR 

T-cells for solid tumor cells. 

Two of the major barriers CAR T-cells present when it comes to their use with solid 

tumor cancers are toxicity and tumor heterogeneity. Some of the new developments in CAR T-

cell therapy such as suicide gene switches and bispecific T-cell engagers show a lot of promise 

that these obstacles can be overcome. 

With the treatment of any disease, the more options the better. What works for one patient 

might not be the best fit for another. CAR T-cells are a welcome addition to the lineup of cancer 

treatments with the improvements and differences they provide. 

17 

 
 
 
 
 
 
BIBLIOGRAPHY 

1.  American Cancer Society. Cancer Facts & Figures 2024. Atlanta: American Cancer 

Society; 2024. 

2.  Asmamaw Dejenie, T., Tiruneh G/Medhin, M., Dessie Terefe, G., Tadele Admasu, F., 

Wale Tesega, W., & Chekol Abebe, E. (2022). Current updates on generations, 
approvals, and clinical trials of CAR T-cell therapy. Human Vaccines & 
Immunotherapeutics, 18(6), 2114254. https://doi.org/10.1080/21645515.2022.2114254 

3.  Choi, G., Shin, G., & Bae, S. (2022). Price and Prejudice? The Value of Chimeric 
Antigen Receptor (CAR) T-Cell Therapy. International Journal of Environmental 
Research and Public Health, 19(19), 12366. https://doi.org/10.3390/ijerph191912366 

4.  Daei Sorkhabi, A., Mohamed Khosroshahi, L., Sarkesh, A., Mardi, A., Aghebati-Maleki, 
A., Aghebati-Maleki, L., & Baradaran, B. (2023). The current landscape of CAR T-cell 
therapy for solid tumors: Mechanisms, research progress, challenges, and 
counterstrategies. Frontiers in Immunology, 14, 1113882. 
https://doi.org/10.3389/fimmu.2023.1113882 

5.  Debela, D. T., Muzazu, S. G., Heraro, K. D., Ndalama, M. T., Mesele, B. W., Haile, D. 
C., Kitui, S. K., & Manyazewal, T. (2021). New approaches and procedures for cancer 
treatment: Current perspectives. SAGE Open Medicine, 9, 20503121211034366. 
https://doi.org/10.1177/20503121211034366 

6.  Guzman, G., Reed, M. R., Bielamowicz, K., Koss, B., & Rodriguez, A. (2023). CAR-T 
Therapies in Solid Tumors: Opportunities and Challenges. Current Oncology Reports, 
25(5), 479–489. https://doi.org/10.1007/s11912-023-01380-x 

7.  Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of Cancer: The Next Generation. 

Cell, 144(5), 646–674. https://doi.org/10.1016/j.cell.2011.02.013 

8.  Jackson, H. J., Rafiq, S., & Brentjens, R. J. (2016). Driving CAR T-cells forward. Nature 
Reviews. Clinical Oncology, 13(6), 370–383. https://doi.org/10.1038/nrclinonc.2016.36 

9.  Kamdar, M., Solomon, S. R., Arnason, J., Johnston, P. B., Glass, B., Bachanova, V., 

Ibrahimi, S., Mielke, S., Mutsaers, P., Hernandez-Ilizaliturri, F., Izutsu, K., 
Morschhauser, F., Lunning, M., Maloney, D. G., Crotta, A., Montheard, S., Previtali, A., 
Stepan, L., Ogasawara, K., … Abramson, J. S. (2022). Lisocabtagene maraleucel versus 
standard of care with salvage chemotherapy followed by autologous stem cell 
transplantation as second-line treatment in patients with relapsed or refractory large B-
cell lymphoma (TRANSFORM): Results from an interim analysis of an open-label, 
randomised, phase 3 trial. The Lancet, 399(10343), 2294–2308. 
https://doi.org/10.1016/S0140-6736(22)00662-6 

18 

 
 
 
10. Kankeu Fonkoua, L. A., Sirpilla, O., Sakemura, R., Siegler, E. L., & Kenderian, S. S. 
(2022). CAR T cell therapy and the tumor microenvironment: Current challenges and 
opportunities. Molecular Therapy - Oncolytics, 25, 69–77. 
https://doi.org/10.1016/j.omto.2022.03.009 

11. Kolb, H., & Holler, E. (1997). Hematopoietic transplantation: State of the art. Stem Cells, 

15(S2), 151–158. https://doi.org/10.1002/stem.5530150819 

12. Marra, J. S., Mendes, G. P., Yoshinari, G. H., da Silva Guimarães, F., Mazin, S. C., & de 
Oliveira, H. F. (2019). Survival after radiation therapy for high-grade glioma. Reports of 
Practical Oncology and Radiotherapy: Journal of Greatpoland Cancer Center in Poznan 
and Polish Society of Radiation Oncology, 24(1), 35–40. 
https://doi.org/10.1016/j.rpor.2018.09.003 

13. Martínez Bedoya, D., Dutoit, V., & Migliorini, D. (2021). Allogeneic CAR T Cells: An 
Alternative to Overcome Challenges of CAR T Cell Therapy in Glioblastoma. Frontiers 
in Immunology, 12, 640082. https://doi.org/10.3389/fimmu.2021.640082 

14. Moghanloo, E., Mollanoori, H., Talebi, M., Pashangzadeh, S., Faraji, F., Hadjilooei, F., 

& Mahmoodzadeh, H. (2021). Remote controlling of CAR-T cells and toxicity 
management: Molecular switches and next generation CARs. Translational Oncology, 
14(6), 101070. https://doi.org/10.1016/j.tranon.2021.101070 

15. Mohammed, S., Dinesan, M., & Ajayakumar, T. (2022). Survival and quality of life 

analysis in glioblastoma multiforme with adjuvant chemoradiotherapy: A retrospective 
study. Reports of Practical Oncology and Radiotherapy: Journal of Greatpoland Cancer 
Center in Poznan and Polish Society of Radiation Oncology, 27(6), 1026–1036. 
https://doi.org/10.5603/RPOR.a2022.0113 

16. National Cancer Institute. (2021). Annual Report to the Nation Part 2: Patient economic 

burden of cancer care more than $21 billion in the United States in 2019. U.S. 
Department of Health and Human Services, National Institutes of Health. 
https://www.cancer.gov/news-events/press-releases/2021/annual-report-nation-part-2-
economic-burden 

17. National Cancer Institute. (2022). CAR T Cells: Engineering Patients’ Immune Cells to 

Treat Their Cancers. U.S. Department of Health and Human Services, National Institutes 
of Health. https://www.cancer.gov/about-cancer/treatment/research/car-t-cells 

18. National Cancer Institute. (2022). Should CAR T Cells Be Used Earlier in People with 
Non-Hodgkin Lymphoma? U.S. Department of Health and Human Services, National 
Institutes of Health. https://www.cancer.gov/news-events/cancer-currents-blog/2022/nhl-
car-t-cells-belinda-transform-zuma7 

19. Newick, K., Moon, E., & Albelda, S. M. (2016). Chimeric antigen receptor T-cell therapy 

for solid tumors. Molecular Therapy - Oncolytics, 3, 16006. 
https://doi.org/10.1038/mto.2016.6 

19 

 
 
20. Orosco, R. K., Tapia, V. J., Califano, J. A., Clary, B., Cohen, E. E. W., Kane, C., 

Lippman, S. M., Messer, K., Molinolo, A., Murphy, J. D., Pang, J., Sacco, A., Tringale, 
K. R., Wallace, A., & Nguyen, Q. T. (2018). Positive Surgical Margins in the 10 Most 
Common Solid Cancers. Scientific Reports, 8(1), 5686. https://doi.org/10.1038/s41598-
018-23403-5 

21. Rohit Reddy, S., Llukmani, A., Hashim, A., Haddad, D. R., Patel, D. S., Ahmad, F., Abu 
Sneineh, M., & Gordon, D. K. (2021). The Role of Chimeric Antigen Receptor-T Cell 
Therapy in the Treatment of Hematological Malignancies: Advantages, Trials, and 
Tribulations, and the Road Ahead. Cureus, 13(2), e13552. 
https://doi.org/10.7759/cureus.13552 

22. Subklewe, M., von Bergwelt-Baildon, M., & Humpe, A. (2019). Chimeric Antigen 

Receptor T Cells: A Race to Revolutionize Cancer Therapy. Transfusion Medicine and 
Hemotherapy: Offizielles Organ Der Deutschen Gesellschaft Fur Transfusionsmedizin 
Und Immunhamatologie, 46(1), 15–24. https://doi.org/10.1159/000496870 

23. Sun, D., Shi, X., Li, S., Wang, X., Yang, X., & Wan, M. (2024). CAR-T cell therapy: A 
breakthrough in traditional cancer treatment strategies (Review). Molecular Medicine 
Reports, 29(3), 47. https://doi.org/10.3892/mmr.2024.13171 

24. Wang, V., Gauthier, M., Decot, V., Reppel, L., & Bensoussan, D. (2023). Systematic 
Review on CAR-T Cell Clinical Trials Up to 2022: Academic Center Input. Cancers, 
15(4), 1003. https://doi.org/10.3390/cancers15041003 

25. Yang, L., Ning, Q., & Tang, S.-S. (2022). Recent Advances and Next Breakthrough in 

Immunotherapy for Cancer Treatment. Journal of Immunology Research, 2022, 8052212. 
https://doi.org/10.1155/2022/8052212 

20