Therapeutic Cancer Vaccines: Mechanism and Clinical Studies

Xiaojun Chen

University of California, Irvine, U.S.A.

Keywords:

Immunotherapy, Cancer, Vaccines.

Abstract:

Cancer, a genetic disease involved in abnormal cell growth and division, is a major cause of mortality

worldwide for centuries. Among various existing cancer treatments, the development of cancer

immunotherapy has been one of the most popular subjects in the field of oncology. Therapeutic cancer

vaccine, an exciting innovation in cancer immunotherapy, has effectively improved the clinical outcome in

patients by overcoming cancer treating barriers that other cancer treatments such as chemotherapy and

radiation cannot achieve, in which tumor cells that are resistant to traditional cancer treatments continue to

proliferate uncontrollably and invade other tissues causing disease relapse or metastases, thus resulting in

toxicity and collateral destruction to normal tissues and affecting patient’s quality of life. The development

of therapeutic cancer vaccines involves numerous factors and requires prudent choice for each step of the

design. This review provides an overview of basic components of therapeutic cancer vaccines including target

antigens and vaccine platforms and analysis of FDA approved therapeutic cancer vaccines as well as those

currently undergoing clinical trials.

1 INTRODUCTION

Cancer is a disease in which body cells abnormally

grow and proliferate and generally develop into

tumors. It is caused by genetic mutations due to cell

division malfunctions, damages to DNA, or genetic

inheritance. Researchers have identified three major

cancer driver genes including proto-oncogenes

involved in normal cell growth and division (Romei

et al, 2016), tumor suppressor genes involved in

regulating cell division and replication (Wang et al,

2019), and DNA repair genes involved in fixing

damaged DNA (Ronen et al, 2001).

The study of cancer therapy has been one of the

most important and popular subjects in the field of

oncology since the 1930s. However, according to the

World Health Organization, there were

approximately 10 million cancer deaths worldwide in

2020 (WHO, 2021). Thus, the development of more

effective cancer treatments is still in urgent need.

Cancer immunotherapy, also known as immuno-

oncology, is one of various existing cancer treatments

that has significantly developed during the past

decades. It aims to prevent, control, and eradicate

cancer by restoring the activity of the patient's own

immune system in which the immune system is

educated to identify and attack specific cancer cells,

immune cells are enhanced to assist cancer

elimination, and the body is provided with additional

components to boost immune responses. Types of

cancer immunotherapy include cancer vaccines

(therapeutic and prophylactic), adjuvants, tumor-

infecting viruses, targeted antibodies, cytokines,

adoptive cell transfer, and checkpoint inhibitors (CRI,

2020). Among the aforementioned cancer

immunotherapies, cancer vaccines development has

been a rapidly growing field of cancer

immunotherapy research since 1990 DeMaria and

Bilusic, 2019).

Cancer vaccines are classified into two categories:

prophylactic and therapeutic cancer vaccines.

Prophylactic cancer vaccines, or preventive cancer

vaccines, are designed to reduce incidence and

morbidity of cancers caused by oncoviruses and has

mechanism similar to normal infectious disease

vaccines in which an inactivated or weakened form of

the disease is introduced to the immune system in

order to educate the immune system to recognize and

eradicate the disease based on their specific antigens,

thus preventing the patient from the disease

(Vanderbilt, 2020). Since prophylactic cancer

vaccines work best in the preventive setting, patients

must receive the vaccine before viral infection. Two

types of prophylactic cancer vaccines are widely

Chen, X.

Therapeutic Cancer Vaccines: Mechanism and Clinical Studies.

DOI: 10.5220/0012021300003633

In Proceedings of the 4th International Conference on Biotechnology and Biomedicine (ICBB 2022), pages 377-385

ISBN: 978-989-758-637-8

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

377

used: HPV vaccine (Cervarix, Gardasil, and

Gardasil-9) which protects against the human

papillomavirus and prevents cervical, vaginal, vulvar,

and anal cancer in women; HBV vaccine (Heplisav-

B) which protects against the hepatitis B virus and

prevents liver cancer (DeMaria and Bilusic, 2019).

In contrast to prophylactic cancer vaccines,

therapeutic or curative cancer vaccines are

administered to patients with existing malignancy.

Therapeutic cancer vaccine comes in two forms, and

its mechanism involves utilizing the adjuvant

vaccination strategies (Melief et al, 2015) (Figure 1).

In one type, malignant cells are removed from a

patient’s tumor. Antigens will then be isolated and

mixed with an adjuvant and made into a vaccine given

back to the patient. By administering the cancer

antigen this way, the patient’s immune system is

primed to recognize the malignant cells as a threat and

thus eradicate the cancer. Another form of therapeutic

cancer vaccines involves removing the dendritic cells

(DCs) from the patient’s blood via leukapheresis and

loading them with cancer antigens ex vivo. Such

antigen-riched dendritic cells will then be infused

back into the patient and trigger an immune response

to the malignant cells (Vanderbilt, 2020) (Melief et

al, 2015). To date, three therapeutic cancer vaccines

have been approved in the United States: BCG for

treating early-stage bladder cancer, Provenge for

treating prostate cancer, and T-VEC for treating

melanoma (DeMaria and Bilusic, 2019).

Figure 1: Mechanisms of Therapeutic Cancer Vaccines (CRI, 2020).

This review elucidates the essential factors in

therapeutic cancer vaccine development including

target antigens and vaccine platforms. Tumor

vaccination targets can be subclassified as either

tumor-associated antigens (TAAs) or tumor-specific

antigens (TSAs), and depending on different causes

of cancer or location of tumor expression, the choice

of target antigens can be varied. Moreover,

therapeutic cancer vaccines can be developed via

different vaccine platforms including cellular

vaccines, viral vector-based vaccines, or molecular

vaccines, and each of the platforms contributes to the

development of therapeutic cancer vaccines uniquely.

Additionally, this review introduces four current FDA

ICBB 2022 - International Conference on Biotechnology and Biomedicine

378

approved therapeutic cancer vaccines including BCG,

Provenge, and T-VEC and provides a summary of

latest cancer vaccines in clinical trials againsting

different cancers including prostate cancer, breast

cancer, pancreatic cancer, colorectal cancer, renal cell

carcinoma, and hematological malignancies.

2 TARGET ANTIGENS

A wide variety of antigens expressed by tumor cells

can be targeted by therapeutic cancer vaccines

(DeMaria and Bilusic, 2019), yet the most imperative

factor when it comes to designing cancer vaccines is

the choice of antigen (Jou et al, 2021) with the ideal

antigens being expressed only by cancer cells,

presented on all cancer cells, highly immunogenic,

and indispensable for ensuring the survival of cancer

cells (Hollingsworth and Jansen, 2019). Tumor

vaccination targets are subclassified as either tumor-

associated antigens (TAAs) (Alatrash et al, 2019) or

tumor-specific antigens (TSAs) (Apavaloaei et al,

2020). Table 1 provides a summary of the differences

between TAAs and TSAs (Wang et al, 2019).

Table 1: TAAs VS. TSAs.

Tumor-associated

antigens (TAAs)

Tumor-specific

antigens (TSAs)

Expressed in

tumor cells?

Yes Yes

Expressed in

normal

cells?

Yes No

Most

common

cause

Post-translational

modifications/Genetic

amplification

Oncogenic driver

mutations that

produce novel

peptide sequences

Target types

Overexpressed

antigens

Differentiation

antigens

cancer/testis antigens

Oncogenic viral

antigens

Shared

neoantigens

Private

neoantigens

2.1 Tumor-Associated Antigens (TAAs)

TAAs are self-antigens expressed abnormally in

malignant cells and at low levels in normal cells

(Alatrash et al, 2019). TAAs target types include:

overexpressed antigens, cell lineage differentiation

antigens, and cancer/testis antigens (CT antigens)

(Table 1). Overexpressed antigens are a broad

category that encompasses any protein discovered in

higher concentrations in tumors than in healthy cells

and tissues (Bright et al, 2014). Examples of antigens

that are overexpressed in malignant cells include

MUC-1, mesothelin, HER2, hTERT. Cell lineage

differentiation antigens such as glycoprotein 100

(gp100), prostatic acid phosphatase (PAP), prostate-

specific antigen (PSA), and melanoma antigen

detected by T-cell 1 (MART-1) are generally not

expressed in adult tissue. CT antigens are usually only

seen in male germ cells, examples including human

melanoma antigen A1 (MAGE-A1), human

melanoma antigen A3 (MAGE-A3), and New York

esophageal carcinoma antigen 1 (NY-ESO-1)

(DeMaria and Bilusic, 2019) (Hollingsworth and

Jansen, 2019).

Several obstacles must be overcome in order to

develop effective therapeutic cancer vaccines against

TAAs. Foremost, growth and activation of self-

antigen-reactive T cells, particularly low-affinity T

cells, must be boosted through utilization of strong

adjuvants, co-stimulators, or repeated vaccination

because the high-affinity B cells and T cells for

recognizing these self-antigens may be inadequate to

trigger immune responses due to central and

peripheral tolerance mechanisms. Therefore,

therapeutic cancer vaccines utilizing TAAs must

elicit the remaining low affinity T cells for the

purpose of “breaking” the tolerance mechanisms (Jou

et al, 2021) (Hollingsworth and Jansen, 2019).

2.2 Tumor-Specific Antigens (TSAs)

TSAs are exclusively expressed by malignant cells,

and because of such tumor-specific properties, unlike

TAAs, TSAs are able to strongly trigger high-affinity

T cells and are less likely to be impacted by central

tolerance and autoimmunity. TSAs consist of

antigens expressed by neoantigens and oncoviruses

(Table 1) due to genetic modifications,

nonsynonymous mutations, or virally transmitted

genetic information in malignant cells (Jou et al,

2021).

Examples of oncogenic viral antigens include the

cervical cancer’s antigens, E7 and HPV E6. An

estimated 10-15 percent of human cancers worldwide

arise from viral infection (Liao, 2006), and such

highly immunogenic alien antigens are indeed the

cause of oncogenesis. Various highly effective

prophylactic antiviral vaccines have been developed

for preventing infections including HPV and HBV

vaccines; however, such vaccines have not proven to

be beneficial in the treatment of cancer that has

already developed, mainly due to the incapability of

humoral immunity to effectively eradicate vast

numbers of virus-infected malignant cells thus

Therapeutic Cancer Vaccines: Mechanism and Clinical Studies

379

requiring cell-mediated immune response

(Hollingsworth and Jansen, 2019).

Even if oncogenic viral antigens are unique to

specific tumor types, they are prevalent across many

patients. Comparably, some neoantigens may occur

in many tumor types and in many patients, hence the

so-called shared neoantigens; whereas, most

neoantigens are exclusively expressed in an

individual patient’s tumor, and they are referred to as

private neoantigens (Hollingsworth and Jansen,

2019). Thus, generation of personalized therapy is

essential for developing a cancer vaccine against an

individual patient’s private neoantigens. The process

of such personalized approach includes sequencing

the patient’s tumor genome, recognizing and

identifying the mutations, predicting neoantigens

utilizing computer-operated algorithms, developing a

personalized vaccine with the predicted neoantigen,

and eventually delivering the vaccine to the patient

(Kreiter et al, 2015).

3 VACCINE PLATFORMS

Anticancer therapy has been tested on a variety of

vaccine designs. These vaccines aim to induce

activation, proliferation, and maturation of T and B

cells by introducing tumor-associated peptides

complexed with major histocompatibility complex

(MHC) molecules to cognate receptors on T and B

cells. Antitumor immune responses are effective with

the present of T cells as tumor antigens are often

generated from intracellular proteins. Improved

understanding of T cell activation and activity has

aided recent developments in therapeutic cancer

vaccine innovations (Hollingsworth and Jansen,

2019). Generally, platforms of therapeutic cancer

vaccines are classified as: cellular vaccines, viral

vector-based vaccines, and molecular vaccines

(Peptide, DNA, or RNA) (Jou et al, 2021).

3.1 Cellular Vaccines

Cellular vaccines refers to cell-based vaccines that are

developed utilizing autologous patient-derived tumor

cells or allogeneic tumor cell line-derived cells (Jou

et al, 2021) (Le et al, 2010) and can be administered

to patients utilizing cell lysates or irradiated whole-

tumor cells (Srivatsan et al, 2014). GVAX vaccine is

an example of cellular vaccine utilizing genetically

modified whole-tumor cells (Jou et al, 2021) to

secrete Granulocyte-macrophage colony-stimulating

factor (GM-CSF), which is a cytokine that boost the

activation of dendritic cells and facilitates antigen

presentation to both T and B cells thus stimulating the

immune system against malignant cells (Nemunaitis,

2005). GVMAX vaccines have shown promising

efficacy in stimulating immune system responses and

inducing tumor regression, yet several clinical studies

demonstrate that GVAX vaccines have limited

effectiveness in prostate cancer, pancreatic cancer,

lung cancer, and melanoma (Hollingsworth and

Jansen, 2019). Autologous dendritic cells (DCs) are

also utilized for cellular cancer vaccine development

as they act as tumor antigen consumers, processors,

and presenters (Jou et al, 2021), and they are either

pulsed with peptide antigen or infected with a viral

vector. Sipuleucel-T (Provenge) is a conventional

cancer vaccine for treating metastatic castration-

resistant prostate cancer (mCRPC) (DeMaria and

Bilusic, 2019). Researchers are currently developing

and inspecting other DC vaccines with one instance

being the adenovirus MART-1-engineered

autologous DC vaccine for treating metastatic

melanoma (Butterfield et al, 2008). Other cellular

vaccines utilized microorganisms to deliver tumor

antigens and elicit immune responses (Jou et al, 2021)

(DeMaria and Bilusic, 2019) (Hollingsworth and

Jansen, 2019).

3.2 Viral Vector-Based Vaccines

Several viruses have been utilized to develop

therapeutic cancer vaccines. Such viral vector-based

vaccines exploit genetically modified versions of

different viruses as vectors and are constructed to

eliminate and replicate within malignant cells (Jou et

al, 2021). An advantage for viral vector-based

vaccines is that the patient’s immune system is able

to respond and recognize viruses efficiently, with

both adaptive and innate immune systems

collaborating to produce robust and substantial

responses. Pattern recognition receptors (PRRs) will

activate antigen-presenting cells in response to viral

pathogen-associated molecular patterns

(Hollingsworth and Jansen, 2019). However, repeat

vaccination will be limited due to the fact that such

viral vectors are neutralized by antiviral immune

response. A common approach to address this

advantage is the application of a heterologous prime-

boost strategy in which one virus vector delivers a

tumor antigen first, followed by a boost with the same

tumor antigen carried by a different viral vector (Pan

et al, 2020).

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3.3 Molecular Vaccines

There are three types of molecular vaccines based on

the source of tumor antigen delivery: peptide, DNA,

and RNA. And each of these three vaccine platforms

have the ability to elicit significant T cell responses as

well as therapeutic effects against established

diseases (Li et al, 2014). Figure 2 provides a

simplified illustration of the three different

therapeutic cancer vaccine delivery types.

Peptide-based vaccines, also known as synthetic

long peptide (SLP) vaccines, relies on usage of exact

MHC class I-binding short peptide fragments to

design the elicitation of high targeted immunological

responses thus avoiding reactogenic sequences

(Bijker et al, 2008). However, single antigen-based

short peptides may fail to overcome loss of antigen

expression within the tumor or fail to encode

sufficient antigenic material to stimulate potent

immune responses, thus immune adjuvant is usually

required for developing peptide vaccines (DeMaria

and Bilusic, 2019). Short peptides, usually less than

fifteen amino acids, can bind toMHC class I

molecules and do not necessitate processing by

antigen-presenting cells. Nevertheless, T cell

dysfunction and tolerogenic signal might occur if

such short peptides bind to other cells that do not

provide correct co-stimulation (Overwijk, 2017).

Moreover, C4 helper T cells will not be activated by

short peptides. Researchers have put effort into

improving peptide vaccines’ quality by utilizing

amphiphilic peptides and combining them with other

immune modulators (Lysén et al, 2020).

DNA vaccines have built-in adjuvants such as

CpG (TLR9) (Li et al, 2014) and represent a

condensed conformation of TAAs, yet they require

additional transcriptional and translational steps

before being cross-represented on DCs (Sahin et al,

2017). Furthermore, DNA vaccines can be

electroporated at the injection location directly. When

administered at high dosages by intramuscular

injection combined with electroporation, DNA

vaccines are the most efficient in generating sufficient

antigen processing and presentation to induce CD8+

T and CD4+T responses (Li et al, 2014). A further

innovation of CD8+ T cell induction is a technique in

neoepitope-specific vaccines in which antibody

response and T cells are boosted due to co-expression

of DNA and chemokines for targeting specific

dendritic cell subsets (Ewer et al, 2016).

Figure 2: Simplified illustration of three therapeutic cancer vaccine delivery types (Li et al, 2014).

Similar to DNA vaccines, RNA vaccines have

built-in adjuvants such as dsRNA and ssRNA.

Nonetheless, in contrast to DNA vaccines, RNA

vaccines do not require an extra transcriptional

process. Thus, they are closer to protein antigen

expression and presentation on MHC molecules (Li

et al, 2014). RNA vaccines can be injected into lymph

nodes directly or intravenously injected with the help

of recently created nanoparticles (lipoplexes)

(Fletcher, 2019). The majority of RNA vaccines in

clinical studies nowadays have utilized mRNA while

the use of RNA replicon is also being investigated

(Plosker, 2012).

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381

4 APPROVED THERAPEUTIC

CANCER VACCINES

To date, only three therapeutic cancer vaccines have

been approved and utilized in the United States: BCG

for treating early-stage bladder cancer, Provenge for

treating prostate cancer, and T-VEC for treating

melanoma (DeMaria and Bilusic, 2019).

4.1 BCG (Baciile Calmette-Guerin;

Sanofi Pasteur)

BCG live, also known as TheraCys and TICE, was

approved by the FDA in 1990 as a cancer

immunotherapy for the treatment of early-stage

bladder cancer. Concretely, it is developed for

intravesical utilization for treating and preventing

urothelial carcinoma in situ of the urinary bladder and

primary Ta or T1 urothelial carcinoma after

transurethral resection (DeMaria and Bilusic, 2019).

Healthcare professionals will administer BCG as a

liquid drug into the patient’s bladder via a catheter.

Such an approach enables direct contact of the drug

and the cancer cells in the bladder thus ensuring the

right target for the patient’s immune system.

However, BCG immunotherapy can cause various

side effects which include urinary tract infection,

blood in the urine, discomfort in the bladder, etc

(Anassi and Ndefo, 2011). According to research, in

patients with superficial bladder cancer who undergo

maintenance treatment, intravesical BCG remarkably

lowers the likelihood of progression following

transurethral resection (DeMaria and Bilusic, 2019).

4.2 Provenge (Sipuleucel-T; Dendreon

Corporation)

Provenge, also known as Sipuleucel-T, was approved

by the FDA in 2010 as an autologous cellular

immunotherapy for treating metastatic castration-

resistant prostate cancer (mCRPC), which is a form

of advanced prostate cancer (DeMaria and Bilusic,

2019). Provenge is developed to activate T cell

response against prostatic acid phosphatase (PAP),

which is an antigen expressed in most prostate

cancers yet not in non-prostate tissues. It is an

effective personalized vaccine therapy in which each

treatment dose is designed specifically for each

individual patient utilizing the patient’s own immune

system. Patient’s immune cells, concretely

autologous peripheral blood mononuclear cells, will

be collected through leukapheresis, and these immune

cells will be combined with a protein (Conry et al,

2018) that triggers the immune cells to detect prostate

cancer. Provenge only has mild to moderate side

effects that usually last one to two days. Researches

have shown with the help of provenge, men with

prostate cancers are able to live longer, and the risk of

death due to prostate cancer has been reduced (The

ASCO Post, 2019).

4.3 T-VEC (talimogene laherparepvec;

Amgen)

Imlygic, also known as talimogene laherparepvec or

T-VEC, was approved by the FDA in 2015 for treating

advanced melanoma. It is also the first oncolytic viral

therapy in the United States (DeMaria and Bilusic,

2019) in which an oncolytic herpes virus, a virus that

only infects cancer cells, is utilized. Such oncolytic

virus is genetically modified to ensure its replication

within tumors and production of the granulocyte-

macrophage colony stimulating factor (GM-CSF).

Usually, talimogene laherparepve is injected directly

into the detected lymph nodes, subcutaneous lesions,

or skin lesions that surgery cannot remove.

Talimogene laherparepvec injected into the tumor

will break down the tumor cells and release tumor-

derived antigens. Such tumor-derived antigens

together with GM-CSF can stimulate the immune

response against the tumor. Side effects of this

therapy include fatigue, chills, fever, nausea,

vomiting, diarrhea, constipation, abdominal pain,

dizziness, injection site pain or inflammation, etc

(Melero et al, 2014). According to research,

talimogene laherparepvec has effectively treated

approximately 40% of patients with surgically

unremovable tumors (Geary and Salem, 2013).

5 CURRENT THERAPEUTIC

CANCER VACCINES

UNDERGO CLINICAL TRIALS

Researchers are currently investigating more possible

therapeutic cancer vaccines for different types of

cancer which include prostate cancer, breast cancer,

pancreatic cancer, colorectal cancer, renal cell

carcinoma, hematological malignancies, etc

(Wittendorf et al, 2012).

As aforementioned, Provenge (sipuleucel-T) is a

currently utilized therapeutic cancer vaccine for

treating patients with spreaded prostate cancer.

Recent studies are investigating and developing

therapeutic cancer vaccines for early-stage prostate

cancer treatments (Wittendorf et al, 2012) (Middleton

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382

et al, 2013). Current clinical trials are investigating

HER2-derived peptides along with additional

immunostimulatory agents including Granulocyte-

macrophage colony-stimulating factor (GM-CSF),

cyclophosphamide, or poly-ICLC. Research has

shown that directly against HER2-derived peptides

via active immunotherapy have beneficial effects for

women with breast tumors with low level HER2

(Wittendorf et al, 2012) (Cancer.NET, 2020).

Telomerase peptide vaccine GV1001 and the

allogeneic tumor-cell vaccine algenpantucel-L are the

most commonly investigated cancer

immunotherapies for pancreatic cancer treatment.

Several phase III and II studies had promising early-

phase trials yet failed in the later stage trials (Amin et

al, 2013).

Current clinical studies on colorectal cancer

treatments involves developing therapeutic cancer

vaccines to educate the immune system to combat

cells with antigens include carcinoembryonic antigen

(CEA), MUC1, guanylyl cyclase C, and NY-ESO-1

(Wittendorf et al, 2012) (Keiholz et al, 2009). AGS-

003 is a current immunotherapy development for

treating renal cell carcinoma (RCC), it is a

personalized therapy utilizing DCs transfected with

patient-specific cancer cell RNA and a truncated,

synthetic human CD40 ligand (Wittendorf et al,

2012).Current clinical studies on hematological

malignancies treatments involve developing

therapeutic cancer vaccines to educate the immune

system to combat cells with antigens include WT1,

MAGE, MUC1 and the preferentially expressed

antigen of melanoma (PRAME) (Wittendorf et al,

2012).

6 CONCLUSION

The development of therapeutic cancer vaccines have

improved the field of cancer immunotherapy

tremendously. As a result of the development of three

FDA approved therapeutic cancer vaccines, which

include BCG, Provenge, and T-VEC, our

understanding of the tumor biology as well as

pathways of the immune system have reached the

next level.

Despite the fact that therapeutic cancer vaccine

development has had promising achievement and

considerable results in most phase I and some phase

II clinical trials, the vast majority of therapeutic

cancer vaccines have failed to exhibit clinical

improvements in phase III trials over the past years

due to low immunogenicity of tumor antigens,

difficulty in targeting established tumor, and

immunosuppressive tumor microenvironment. Thus,

testing therapeutic cancer vaccines in early stages of

cancer to minimize the disease burden and immune

tolerance should be prioritized. Moreover, it’s

essential to establish better strategies of incorporating

therapeutic cancer vaccines into the standard

treatment such that immune tolerance is less

formidable or combining therapeutic cancer vaccines

with other cancer treatment therapies thus promoting

synergistic treatment effects.

Developing personalized therapeutic cancer

vaccines is a difficult task overall. Fortunately,

researchers are still indefatigably investigating

potential solutions to the aforementioned challenges

and examining more therapeutic cancer vaccines in

clinical trials. It is undoubtedly that more therapeutic

cancer vaccines can be approved in the future.

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