Cytokines in Cancer Immunotherapy

Menghan Liu

1,*,†

, Yuanyuan Pang

2,†

and Xinyang Wan

3,†

Wellington College International Tianjin, Tianjin 300120, China

Department of Chemistry, University of Washington, Seattle 98195, U.S.A.

Macleans College, Auckland 2012, New Zealand

Keywords:

Cancer, Cytokines, Immunotherapy.

Abstract:

Cytokine immunotherapy is a widely concerned field in cancer treatment. As proteins of the immune system,

cytokines can regulate the immune response of the host to tumor cells and directly induce tumor cell death.

However, there are some limitations in the treatment of cytokines. On the one hand, low dose single drug

therapy of cytokines has no significant therapeutic effect; on the other hand, high dose therapy may cause a

variety of side effects due to the pleiotropic effect of cytokines. The involvement of cytokines in pro-tumor

and anti-tumor immune responses remains an urgent issue. This article mainly introduces the application of

cytokines in cancer treatment. Although the efficacy of early stage cytokines in cancer treatment is modest,

advances in molecular biology and genomics are expected to optimize and enhance cytokine therapy in

clinical practice in the future.

1 INTRODUCTION

Cancer immunotherapy is one of the most effective

ways to help the immune system recognize and fight

cancer cells (Conlon, K. C. et al. 2019). Cytokines

promote the function of the immune system in cell

signaling.

Autocrine is where cytokines act on the mother

cell that secretes them, while paracrine is where

cytokines may act on nearby cells. Endocrinology is

caused by the action of cytokines on distant cells. The

types of cytokines identified include chemokines,

interferon (INF), interleukins (ILs), colony

stimulating factors (CSFs), tumor necrosis factors

(TNFs), transforming growth factors (TGFs),

lymphocytokines, and single cytokines. There are

also artificially produced interleukins that can be used

to treat alder interleukin cancer. These cytokines can

be roughly divided into three categories according to

their roles and functions. Lymphokines and single

cytokines are produced by immune system cells and

are involved in various aspects of immune function.

The second and third groups include growth factors

and colony-stimulating factors, which control tissue

growth and blood cell proliferation. Chemokines are

produced by chemotactic activity and are involved in

†

These authors contributed equally

the regulation of the immune system.

Cytokines act

through cell surface receptors and modulate the

balance between humoral and cell-mediated

immunity. They are produced by a range of cells,

including B lymphocytes, T lymphocytes,

macrophages, mast cells, endothelial cells, fibroblasts

and stromal cells. The cytokines have effects of

pleiotropism, which means that one cytokine that

binds to different targets can produce different

effects. For example, the activated T helper cell can

produce IL-4, which can bind to B cells, thymocytes

and mast cells. The IL-4 can induce activation,

proliferation, and differentiation on B cells. However,

it can only induce proliferation on thymocytes and

mast cells. Another property of some cytokines is

redundancy. Multiple cytokines may have the same

effects on the same target. As an example, the

activated T helper cell can produce IL-2, IL-4, IL-5 at

the same time. If they all bind to the receptor on B

lymphocytes, they may induce the same function of

proliferation. In addition, some cytokines can

influence the activity of other cytokines in different

ways, and they can also act synergistically or

antagonistically (Zhang, J. M., & An, J. 2007).

In this review, it mainly focused on 5 concepts,

including the discovery of cytokine immunotherapy,

Liu, M., Pang, Y. and Wan, X.

Cytokines in Cancer Immunotherapy.

DOI: 10.5220/0012020900003633

In Proceedings of the 4th International Conference on Biotechnology and Biomedicine (ICBB 2022), pages 343-351

ISBN: 978-989-758-637-8

 2023 by SCITEPRESS – Science and Technology Publications, Lda. Under CC license (CC BY-NC-ND 4.0)

343

the mechanism of cytokines, interleukins and

interferons and their targeted cancer, the current

progress and issues of cytokine immunotherapy, and

the predicted improvements.

2 THE DISCOVERY OF

CYTOKINES

Cytokines play an important role in the diagnosis,

prognosis and treatment of human diseases

(Dinarello, C. A. 2007). IL-2 was the first cytokine

found to have therapeutic effects, significantly

stimulating the growth of T cells and natural killer

cells (Robert Gallo, M. D. et al. 1976).

IL-2 successfully treated patients with advanced

metastatic renal cell carcinoma and melanoma.

Currently, researchers are focusing on whether IL-2

is effective in combination with other cytokines in

these cancer patients (Jiang, T., Zhou, C., & Ren, S.

2016). IL-7 is a major regulator of T cell homeostasis.

The cytokine driven regeneration of T cells was

demonstrated in the first human clinical trial using IL-

7, and IL-7-based therapies may also restore immune

function in other immunocompromised individuals,

such as those living with HIV and the elderly, and

may enhance the efficacy of vaccines and other

cancer immunotherapies

(Fry, T. J., & Mackall, C. L.

2002). Similar to IL-2, IL-15 triggers the production

of immune cells that attack and kill cancer cells.

Results from the first human clinical trial showed that

IL-15 significantly increased T and NK cell growth

and activity. IL-15 is currently being investigated for

its potential to enhance the effectiveness of vaccines

against viruses that cause cancer and autoimmune

diseases (Mackall, C. L. et al. 2011).

3 MECHANISM OF CYTOKINES

Cytokines help the immune system do its job.

Immune cells, cytokines and organs must

communicate with each other to prevent pathogens or

harmful invaders from entering the body. The first

immune cell that notices the pathogen creates and

sends out messages in the form of cytokines to the rest

of the organs or cells in the body, responding directly.

Different types of cytokines will be released into the

blood or directly into tissues, and then, locating the

immune cells that are designed to target and bind to

the cell receptors.

3.1 Jak-STAT Pathway

Cytokines use multiple signaling pathways. One of

the pathways is the Jak-STAT pathway which is

shown in figure 1.

Figure 1: Cytokine signaling through JAK–STAT pathway (Dodington, D. W. et al. 2018).

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The Jak-STAT pathway is a very rapid cytosol-to-

nuclear signaling pathway, and it involves both Janus

kinase protein (JAK) and signaling transducer and

activator protein (STAT). Cytokine molecules first

bind to the receptors and stabilize heterodimer and

bring the JAKs together (Leonard, W. J., & Lin, J. X.

2000). JAK phosphorylates each other which can

increase the activity of the tyrosine kinase domain.

Activation of JAK kinase in turn phosphorylates the

relevant receptor tyrosine residues.

These phosphotyrosines act as docking sites for

STAT proteins

(Greenlund, A. C. et al. 1995). All

STAT share basic features (Darnell, J. E. et al. 1994;

Darnell, J. E. 1997), including an N-terminal domain

(important for dimer formation), a coiled-coil domain

(crucial for dimerization tag and nuclear localization

signal), a DNA binding domain (binding to a specific

DNA sequence), a linker domain, a SH2 domain

(docking STAT to phosphorylated tyrosine residue),

and a C-terminal region that contains a critical

tyrosine residue and a transactivation domain

(Mitchell, T. J., & John, S. 2005). They are then

separated from the receptor to form homo-dimer or

hetero-dimer after they are recruited (Horvath, C. M.,

& Darnell, J. E. 1997). The STAT protein is then

transferred to the nucleus, where it binds the DNA to

the regulatory region of the target gene and regulates

gene expression.

3.2 Inflammation

Cytokines mainly occur when the body is invaded by

pathogens and cause inflammatory responses by

changing the porosity of the blood vessel cell wall and

reducing cell contact area. Blood then leaks into

surrounding tissue, allowing immune cells to enter

the damaged area and begin the healing process (Bio-

Rad. n.d.). The inflammatory response, along with

physical tissue damage, directs brain cells to release

chemicals. Cytokines are essential for a healthy

immune response, but the concentrations need to be

just right. Too high levels can overwhelm the body,

creating a phenomenon known as "cytokine storm."

Cytokine storms usually occur when pathogens enter

the body at the same time, or when the body mis-

produces cytokines early in the immune response.

Every organ has cytokine receptors, and in this case,

oversignaling helps the immune system precisely

clear pathogens. In addition, cytokine storms can

have negative effects on the body. Patients with

bacterial infections often experience cytokine storms,

symptoms of some diseases such as COVID-19.

Cytokine storms participate in an uncontrolled

immune response that causes a decrease in oxygen in

the blood (Ragab, D. et al. 2020). Fluid builds up in

the lungs causing breathing difficulties and nervous

system problems. The brain is naturally protected

from harmful chemicals because of the blood-brain

barrier, but the cytokines are so small that they easily

cross the brain's protective membrane (Manoylov, M.

K. 2020, November 6).

3.3 Network of Pleiotropic Cytokines

The work of different cytokines on different cells can

be concluded in figure 2.

Figure 2: Network of cytokines (Zhang, J.-M., & An, J. 2007).

Cytokines in Cancer Immunotherapy

345

It shows the paracrine signaling network of

different cytokines. Cytokines are pleiotropic, which

means that different cells may secrete the same

cytokines, and a single cytokine may act on different

cells. Cytokines include B cells, T cells,

macrophages, mast cells, neutrophils, basophils, and

eosinophils. Macrophages engulf foreign cells and

present pathogens, use cytokines to stimulate specific

immune responses of B cells and T cells, and activate

non-specific immune responses produced by other

cells (such as natural killer cells). T cells secrete a

variety of factors, interferon and interleukin, which

participate in the immune response of specific

antigens. Proliferation and activation of eosinophils,

neutrophils, and basophils also play a role in

cytokines. They fight cancer by interfering with

cancer cell growth and reproduction, stimulating the

immune system, encouraging killer T cells and other

cells to attack cancer cells, and encouraging cancer

cells to produce chemicals that attract immune cells.

4 INTERLEUKINS AND

INTERFERONS

4.1 Interleukins (ILs)

Interleukins are cytokines involved in the regulation

of immune response, inflammation and

hematopoiesis (Sims, J. E. et al. 1988). A majority of

them are produced by macrophages, CD4+ T cells,

monocytes and endothelial cells, and bind to their

target receptors. They have different effects when

they target different target cells.

IL-2 are secreted by T cells (Th1-cells), and target

on activated cells, macrophages on their receptors of

CD25/IL2RA, CD122/IL2RB, CD132/IL2RG,

resulting in a growth and differentiation (Ymer, S. et

al. 1985). The source cell of IL-2 includes activated

Th cells, mast cells, NK cells, endothelium and

eosinophils. The target cells, including hematopoietic

stem cells and mast cells, have receptors of

CD123/IL3RA, CD131/IL3RB. They will induce the

differentiation and proliferation of myeloid

progenitor cells, and growth and histamine release of

the mast cells (Dorssers, L. et al. 1987).

Other interleukins have different functions by

acting on other leukocytes. As one of the basic

cytokines with multipotency for the resistant

framework, the natural capacity of IL-2 is intervened

by IL-2 receptor, which has a place with type I

cytokine receptor (Lippitz, B. E. 2013).

IL-2 receptor

is a trimer complex made of three subunits α, β, γ.

Binding of IL-2 to its receptor can induce multiple

signaling pathways (STAT, PI3K-Akt and MAPK,

three downstream signaling pathways). Activation of

IL-2 can promote the growth of immune cells and

enhance the activity of immune cells, which can

attack and kill cancer cells (Spolski, R. et al. 2018).

In the 1990s, high doses of IL-2 were approved for

several patients with metastatic melanoma and

metastatic renal cell carcinoma and showed long-

lasting complete responses. In immunotherapy

clinical studies, patients with advanced melanoma

and neurocytoma who have responded to high-dose

IL-2 therapy have been reported to have prolonged

survival of 3-5 years in patients with melanoma and

neurocytoma who have responded to high-dose

interleukin-2 therapy (Chow, S. et al. 2016).

At the

same time, low doses of IL-2 can also treat some

autoimmune diseases. Low doses of IL-2 may be

targeted at the underlying role of Treg cells, leading

to the re-control of autoimmune diseases and

inflammation (Orozco Valencia, A. et al. 2020).

The

FDA first approved recombinant IL-2 as effective

tumor immunotherapy for patients with cancer.

However, severe adverse reactions and priority

amplification of immunosuppressed Treg cells limit

recombinant IL-2 in cancer therapy. In order to

reduce toxicity and prevent the targeting effect of

Treg cells, some newly developed fusion proteins can

improve the efficacy and lower toxicity of tumor

therapy. These include NKTR-214, which has been

shown to mask the region of IL-2Rα interaction with

its six releasable PEG chains, thereby mediating the

preferentially activated effector cells and showing

good tolerability and significant clinical activity in

patients with advanced melanoma. It is reported that

high-dose IL-2 therapy for renal cell carcinoma and

metastatic melanoma showed that about 16% of

patients reacted emphatically to treatment and the

reaction kept going longer in patients with metastatic

melanoma (Clark, J. I. et al. 2021).

The use of high

doses of IL-2 has been associated with severe side

effects, such as encephalitis and meningitis. The

combination of IL-2 agents with other anticancer

immunotherapy agents (such as cell metastasis,

antigen-specific vaccines, and cytotoxic T-cell

associated antigen 4 can further develop therapy

proficiency while lessening IL-2 dosages and

diminishing antagonistic occasions (Dhupkar, P., &

Gordon, N. 2017).

The utilization of IL-2 in

malignant growth, intense leukemia, immune system

illnesses, human immunodeficiency (HIV) and

different infections, among which the therapy of

foundational lupus erythematosus (SLE) has gained

momentous headway (Orozco Valencia, A. et al.

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2020).

At present, IL-2 is an effective and safe

treatment. However, the toxicity of IL-2 is expected

and controllable in clinical medicine. The treatment

of IL-2 without treatment-related death can also be

applied to inflammatory diseases or autoimmune

diseases to improve the therapeutic effect of IL-2-

based cytokine. IL-2 therapy can amplify and activate

effector T cells and NK cells, providing alternative

immunotherapy options for patients following

conventional cancer treatment.

4.2 Interferons (IFNs)

There are two main types of interferons: type I

interferons (IFN-alpha and IFN-beta), type II

interferons (IFN-gamma). Type I interferons are a

group of antiviral cytokines. They are induced during

viral infections by viral replication products (Eg.

double stranded RNA). IFN-alpha is produced by

white blood cells except lymphocytes, whereas IFN-

beta is produced by fibroblasts. These two kinds of

type I interferons are both produced when cells have

been infected by pathogens, as a warning signal to the

body’s immune system. Their main function is to

trigger immune cells (including natural killer cells

and cytotoxic T lymphocytes) to release type II

interferons, also known as IFN-gamma, to fight the

germs. The type II IFNs are produced by increasing

phagocytosis by macrophages. One common function

of these interferons is that they all inhibit viral

replication (Katze, M. et al. 2002). IFN-alpha can also

be used to treat cancers of hairy cell leukemia, chronic

myelogenous leukemia (CML), kidney cancer,

melanoma and so on (American Cancer Society n.d.).

In the late 1980s, cytokine-based immunotherapy

became the primary treatment for locally advanced or

metastatic renal cell carcinoma (RCC) (Koneru, R., &

Hotte, S. J. 2009). The antitumor effect is regulated

by different mechanisms such as immunomodulation,

antiproliferative activity, regulation of gene

differentiation, etc. In the randomized controlled

trials, patients treated with the IFN-alpha subtype

were studied with patients treated with non-IFN-

alpha subtypes as a control group. The result

demonstrated that the IFN-alpha subtype is related to

a more significant remission, indicating a better

efficacy than the control group. The IFN-alpha group

also had lower 1-year mortality. From the research,

there was no difference between the IFN-alpha 2a and

2b subgroups (Coppin, C. et al. 2005). The dose-

response effect regarding the IFN-alpha group

remained unclear. However, with the increased dose,

the toxicity level would be expected to be higher. The

dose might be individualized based on the severity

and the progress of the disease.

IFN-alpha was also an antitumoral agent common

in leukemia; the direct effects include cell growth

inhibition, apoptosis induction, enhancement of acute

myeloid leukemia (AML). The binding of IFN-alpha

regulates these effects to their receptors which can be

expressed on the leukemic cell surfaces. The binding

can activate specific cell signal pathways, including

Jak-STAT pathway activators. Even though people

have understood specific pathways were directly

related to the leukemia treatment, the precise role of

these pathways in AML remained to be researched

(Anguille, S. et al. 2011). AML patients can have

impaired immune function, and some of their immune

responses might not be as intense. Therefore, other

indirect effects of IFN involved activating dendritic

cells, T cells, and natural killer cells, which played a

massive role in antileukemic immune responses. As

for other types of leukemia, such as chronic myeloid

leukemia (CML), IFN was once the best treatment for

CML. However, when tyrosine kinase inhibitors were

invented and used, they became the first-line

treatment, and interferon is rarely used for CML.

The last class of cancer usually treated IFN-alpha

as a single agent was lymphoma. One of the review

articles published in 2003 indicated the IFN as a

single treatment of cutaneous T-cell lymphoma was

efficacious. The IFN was filtered by the glomeruli,

and they can undergo fast proteolytic degradations

during tubular reabsorption (Olsen, E. A. 2003).

One

of the problems with the interferon usage in

lymphoma patients was the development of the

neutralizing antibodies, which might be influenced by

the underlying disease, the dosing regimen of

cytokine-based immunotherapy, or the duration of the

treatment. The presence of the antibody can

essentially decrease the efficacy of the medication in

lymphoma patients. One of the possible reasons for

the development of antibodies can involve the

overactive immune response. Therefore, people

started to look for other solutions. In 2015, one

randomized controlled trial was done to compare the

concurrent use of IFN-alpha with low doses of

methotrexate or retinoids, which can suppress the

immune system. It was found that the use of IFN with

retinoids or a low dose of the cytotoxic drug can be

preferred in patients with refractory T-cell

lymphoma, and the toxicity was minimal for this

combination (Aviles, A. et al. 2015).

So far, only these three cancer types were using

cytokine-targeted medications for treatment as

monotherapy agents, and people have found other

solutions with the development of the newer

Cytokines in Cancer Immunotherapy

347

medication. As for other cancers such as brain tumors

and phase 1 and 2 clinical studies of IFN were

conducted on patients with malignant brain tumors.

People did find some of the patients have shown

improved disease states. However, the effect

remained in the local area, and it did not show the

systemic effect, so it failed to move onto the next

stage (Nagai, M., & Arai, T. 1984). Due to the lack of

response to monotherapy, people, in general, do not

use them. Still, since they are immunomodulators and

they can influence the immune response in general,

IFN combination with radiotherapy or chemotherapy

brought people's interest. People have done an

investigation on combination therapy.

5 THE CURRENT PROGRESS

AND ISSUE OF CYTOKINES

At the laboratory level, experiments on mice

demonstrated that the cytokines had a preclinical

effect. Interferon can treat hair cell leukemia and

interleukin can treat advanced melanoma and

metastatic kidney cancer. IL-12, IL-15, IL-21 and

granulocyte macrophage colony stimulating factors

have also been used in clinical trials. Despite this,

cytokine as a monotherapy did not fulfill its early

promise, because parenteral administration of

cytokine did not reach sufficient concentrations in

tumors. Increased cytokine concentration may

indicate an uncontrolled immune response, which is

called cytokine release syndrome or cytokine storm.

This can lead to severe inflammation, shock,

respiratory failure, organ failure, and in some cases

even death (Waldmann T. A. 2018).

As previously discussed, cytokine-based therapy

indicated antitumor characteristics; people further

found the effect was achieved by inhibiting

proliferative effects on cells, so tumor cells were not

growing as fast. Meanwhile, they also indirectly

stimulated our immune system, which can kill tumor

cells. Therefore, the mechanism included two

perspectives. The first is to decrease cancer cells'

growth and increase the immune system to get rid of

them. There are multiple cytokines found that have

therapeutic effects. However, more specifically for

cancer, only IL- 2 and IFN-alpha demonstrated

antitumor effects and the FDA approved them for the

treatment of cancers. The other cytokines, such as IL-

17, can be used for the treatment of autoimmune

diseases like psoriasis. Even though the antitumor

effects were not as desired due to the low efficacy,

they showed better outcomes when using other

anticancer agents. The combination therapy showed a

more promising effect than the monotherapy.

There are a few barriers related to these

medications, and some of them should be further

developed. One of the most significant issues with

these medications was the low efficacy while having

high toxicities. One of the guesses related to the high

kidney response and low liver response might relate

to the pharmacokinetics of this class of medication.

They are mainly renally cleared and the liver

clearance was minimal. The major toxicities involved

the loss of appetite, high infection risk, flu-like

symptoms such as fever, chills, and fatigue. All of

these could be very common, and people might see

them in patients on cytokine-based immunotherapy.

The possible further research can focus on improving

pharmacokinetics and pharmacodynamics, improving

local reaction instead of a systemic reaction, and

optimizing the combination therapy to achieve better

outcomes. In general, cancer cells can develop

multiple different mechanisms to fight against drugs

and survive, including the inhibition of apoptosis,

drug expulsion, and increased proliferation. Recent

studies have found unregulated cytokine expressions

are highly involved in the drug resistance mechanism

(Jones, V. S. et al. 2016).

Even though IFN-alpha and IL-2 do not provide

very effective clinical outcomes, they are excellent

candidates for combination therapy with other agents.

In the past clinical trial, it was studied in the patients

with hepatocellular carcinoma, which was not one of

the diseases treated with IFN-alpha. In this trial, 106

patients with hepatocellular carcinoma received 5

million units of IFN-alpha on day 1,3,5 and each

week of the treatment; meanwhile, they also received

5-fluorouracil (5-FU) 500mg on day 1-5 during the

first two weeks of the 4-week cycle. The 5-FU is a

standard medication used in hepatocellular

carcinoma, so in the trial, people compared the

combination with IFN-alpha with the standard

therapy alone from the historical data. It turned out,

about 20% of patients in the treatment group showed

complete response and 36% of patients showed

partial response. The efficacy was improved

significantly compared to the standard therapy alone.

The survival rate at 1-year and 2-year time points

were 34% and 18%, while historically, with patients

treated with standard therapy, the survival rate was

15% and 5%. Therefore, the survival rate largely

improved with the combination of IFN-alpha, and the

combination therapy was safe and more clinically

effective (Obi, S. et al. 2006). From this example, the

future of this class of medication should be

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emphasized on the combination therapy with other

agents due to its unique mechanism of action.

6 PREDICTED IMPROVEMENTS

OF CYTOKINES

The biological basis and rationale of the use of

cytokines are powerful, however, the clinical use of

this technology faces a range of issues. There are

some possible improvements in cytokine technology

which researchers are going to do next. Firstly,

improving pharmacokinetics and pharmacodynamics.

Clinical pharmacology is the study of the interaction

between the human body and drugs.

Pharmacokinetics and pharmacodynamics are the two

main branches of clinical pharmacology.

Pharmacokinetic describes the absorption,

distribution, metabolism, and excretion of drugs

(ADME), while pharmacodynamic describes how

biological processes in the body respond to or are

affected by drugs (Otagiri, M., Imai, T., & Fukuhara,

A. 1999). Pharmacokinetics and pharmacodynamics

were vital in determining the safety and effectiveness

of drugs. Secondly, improving local injection. Some

cytokines can be produced in the laboratory and used

to treat cancer. Some are used to help prevent or

control the side effects of chemotherapy. They are

injected under the skin, into muscles or veins. The

two most common types are interleukins and

interferons (Zhang, Z. & An, J. 2007). IFN-beta can

be injected in areas of the body with a layer of fat

between the skin and muscle, such as the thigh.

However, interferon beta-1a can control the

symptoms, but it cannot cure it. IL-2 and Interferon-

alpha have been combined based on data from

preclinical studies and have shown a synergistic

effect. A review of available phase I and II trials with

more than 1,400 patients indicated a response rate of

approximately 20%, 3% to 5% of patients completely

regressed. In order to prove that this combination

improves the overall response rate, randomized trials

were needed. The result of a phase III study displayed

that, compared with patients who received either

cytokine alone, patients treated with continuous

infusion recombinant (r) IL-2 and subcutaneous IFN-

alpha had a significant improved response rate 18.6%

and 1-year event-free survival 20.9%. The clinical

results are consistent with the improved response rate

in patients receiving rIL-2 and IFN-alpha. Continued

research on novel and new treatment methods

remains a priority (Bukowski R. M. 2000).

Since the 1950s, a variety of cytokines have been

used in the study of preclinical disease models, and

with the development of recombinant protein

technology in the 1980s, some of these cytokines

have become successful biopharmaceutical products.

However, due to cellular pleiotropy, the clinical

translation of these innate immune signaling

molecules is limited and they play primarily local

roles in tissues. In view of the clinical potential and

clinical trials in cancer immunotherapy, a range of

molecular and formulation engineering strategies are

being applied to reduce therapeutic toxicity while

maintaining or enhancing therapeutic efficacy.

Cytokine technology is promised to become more

effective and widespread in the use of clinical

treatment.

7 CONCLUSION

Cytokine therapy to activate the immune system of

cancer patients is an important treatment method. The

generation of a specific, effective cytokine-based

immunotherapy requires a variety of cytokines and

their receptors to combine with each other and give

an optimum effect. Understanding the molecular

signaling pathways of cytokine receptors is critical to

the development of cytokine based cancer therapies.

The most common cancers using cytokine-based

therapy are kidney cancer, leukemia and lymphoma.

These are the only three cancer types that use

cytokine-targeted medications for treatment as

monotherapy agents. This paper is introducing and

comparing three subtypes of interferon in the

treatment of kidney cancer, as well as the role of

antitumor agent IFN-alpha in the treatment of

leukemia and lymphoma. This paper derives from in-

depth research on cytokine-based immunotherapy

and its current barriers to indicate the future

medication development focus using the study of

hepatocellular carcinoma, and the combination

therapy of IFN-alpha and the standard medication 5-

FU on the treatment of hepatocellular carcinoma,

which resulted a higher survival rate. The extensive

pleiotropy and redundancy of cytokine signaling

pathways suggest that cytokine therapy may use

combination regimenes to amplify antitumor

responses, inhibit regulatory pathways, and minimize

toxicity. In general, cytokine based immunotherapy

has shown its great potential, and cytokine therapy

will have a broader prospect in the future.

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349

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