Abstract:
Cancer is disease characterized by uncontrolled cell proliferation. Vaccines exploit the ability of
the human immune system to respond to, and remember, encounters with pathogen antigens
through humoral immunity. Cancer vaccines are an immunotherapeutic approach aimed to assist
the immune system in identifying and disposing of cancerous cells. Cancer immunotherapy
provides a new venue of treatments that stray away from conventional medical and surgical
treatments that carry a large mortality and morbidity burden. Our literature review looked at
literature reviews regarding cancer vaccination in the last 5 years using Google Scholar and
PubMed as databases, while relying on the snowball method to identify relevant sources. Our
search included the key terms: Cancer Vaccine, Cancer Immunotherapy, and Personalized Cancer
Therapy. The review summarizes the main types of cancer vaccines, the basic mechanisms of
cancer vaccines, and their limitations and prospects.
Table of Contents
Abstract: ........................................................................................................................................... 1
1. Introduction: ............................................................................................................................. 3
2. Cancer Vaccine Mechanisms: .................................................................................................. 4
3. Therapeutic Cancer Vaccine Types: ........................................................................................ 5
3.1 Cell-based vaccines: ............................................................................................................... 6
3.2 Microbial-Based Vector Vaccines: ........................................................................................ 6
3.3 Peptide-based Vaccines:......................................................................................................... 7
3.4 Nucleic Acid-Based vaccines:................................................................................................ 7
3.5 Induced stem cell-based vaccines: ......................................................................................... 8
4. Limitations of Cancer Vaccination: ......................................................................................... 9
4.1 Research challenges: .............................................................................................................. 9
4.2 Clinical Considerations: ......................................................................................................... 9
5. Cancer Vaccine Future Prospects: .......................................................................................... 10
6. Conclusion: ............................................................................................................................. 11
7. References .............................................................................................................................. 12
1. Introduction:
Vaccines are considered one of the most important medical advancements of human history,
providing a way not only to treat, but also to prevent illness altogether. With the advent of Edward
Jenner´s small pox vaccine in 1798, began a new era of medicine where disease prevention came
under the spotlight (Iwasaki & Omer, 2020). Cancer is broad term that describes a group of
diseases caused by uncontrolled cell proliferation, leading to localized and systemic symptoms
that vary with cancer type and location. All cancers are caused by DNA alterations, which can be
caused by genetic factors or environmental factors (Brown, et al., 2023). Viruses like Hepatitis B
and C, Human Papilloma virus, and Epstein- Barr virus have been linked to neoplasia.
A tumor microenvironment (TME) is a mixed composition of transforming immune cells, blood
vessels, stromal cells, and extracellular matrix. A fundamental understanding of TME´s is essential
to grasp the factors that impact patient response to treatment (Kaczmarek, et al., 2023). Although
cancer research has led to many advancements in cancer screening and diagnosis; cancer
management remains a challenge utilizing conventional surgical and medical treatments. Some
advancements in medical therapy have led to a spike in the 5-year survival of some cancer patients;
nonetheless, many cancers are still considered fatal (Sakr, et al., 2023).
Immunotherapy and vaccines offer a new prophylactic and therapeutic approach to cancer
treatment, utilizing the humoral immunity´s ability to target specific antigens. Many cancer
vaccines are currently approved and have demonstrated their success, including the Hepatitis B
vaccine and Human Papilloma Virus vaccine (Liu, et al., 2022). Although, on paper, cancer
immunotherapy resembles a miracle approach, many limitations hinder its efficacy and research.
2. Cancer Vaccine Mechanisms:
Cancer can be simply defined as uncontrolled cell growth; however, this definition does not
encompass the complexity of oncology. It must be understood that different tumors express
different factors with varying symptoms, metastasis routes, antigens, and response to host immune
reactions. Therefore, each cancer type has its own classification system, treatment guidelines, and
chemotherapy regimens (Debela, et al., 2021).
Cancer immunotherapy can be classified into two main categories: prophylactic and therapeutic.
Prophylactic vaccines act to prevent cancer formation through eliminating causal factors.
Prophylactic vaccines can target cancer causing organisms, such as the currently available
Hepatitis B vaccine and HPV. They can also aim to target early tumor markers or pathways to
prevent cancer progression (Lin, et al., 2022). Therapeutic vaccines act to directly target already
formed or advanced cancers. The BCG vaccine became the first therapeutic vaccine approved for
bladder cancer treatment in 1990.
Cancer antigen identification and selection is essential for therapeutic cancer immunotherapy. An
ideal antigen should be expressed exclusively in cancer cells, highly immunogenic, and necessary
for cancer cell survival. Cancer vaccines mainly target Tumor-Associated Antigens (TAA) or
Tumor-Specific Antigens (TSA) to induce a host immune response. Despite the fact that cancers
express altered antigens, they have shown to be of low immunogenicity inducing a sub-optimal
cellular and humoral immune response in advanced stages (Stefania, et al., 2021).
TAAs are mostly expressed by tumor cells; nonetheless, can be expressed by healthy cells. TSAs
are expressed only in tumor cells, and form due to genetic mutations absent in healthy cells. This
differentiation is critical to avoid auto-immune disease induction. Individual-based TSAs that form
due to sporadic oncogenic genetic mutations are called neoantigens.
Since TAAs are expressed by healthy cells, they can be used to mass produce predefined vaccines
that target common cancer types present in the population. On the other hand, TSAs and
neoantigens are tumor and individual specific, and can form due to sporadic genetic mutations not
commonly found in the population, requiring personalized antigen identification and vaccine
production. Neoantigen targeting vaccines are proving to be more effective in improving cancer
patient survival. A recent mRNA melanoma vaccine has shown long-term cancer recurrence
prevention (Lu, et al., 2020).
Moreover, adjuvant vaccine components play a key role in enhancing the efficacy of cancer
vaccines. These include: Toll-like receptor agonists (TLR), cytokines, immune checkpoint
inhibitors, Stimulator of Interferon Genes Agonists (STINGs), and saponins. These can act to
prolong antigen availability, activate innate cellular immune response, circumvent local TME
induced immune suppression, and mitigate systemic immune suppression in the context of
combination cytotoxic chemotherapy (Stefania, et al., 2021).
3. Therapeutic Cancer Vaccine Types:
The literature provides a classification of therapeutic cancer vaccine types based on composition
(Tojjari, et al., 2023) (Kaczmarek, et al., 2023) (Fan, et al., 2023). They can be summarized in the
following chart (Chart 1):
Chart 1 (Elsheikh, et al., 2023)
3.1 Cell-based vaccines:
Cell-based vaccines aim to stimulate an immune response through the use of immune cells, most
commonly dendritic cells. Dendritic cells (DC) act as the main antigen presenting cells (APC) in
the human immune system. The production of a DC cell-based vaccine entails the harvest of DCs
and tumor cells from a cancer patient, introducing TAAs or TSAs to DCs, expanding cell
inoculum, and then reintroducing the DCs into host body lymph nodes to induce a T-cell mediated
immune response. A phase-1 trial evaluating a DC-based Hepato-Cellular Cancer (HCC) vaccine
developed using Alpha-Fetoprotein (AFP) as a targeted antigen, has shown encouraging results.
Still, in a general oncology context, only 5-15% of cancer patients are able to benefit from DC
vaccination (Lee, et al., 2023).
Cell-based vaccines can be categorized into allogeneic or autologous. Allogeneic cell-based
vaccines utilize TAAs or TSAss against well-known cancer antigens, offering the prospect of over-
the-shelf cancer vaccines. Autologous cancer vaccines require harvesting of host´s tumor and
immune cells to personalize a vaccine against specific neoantigens.
Cell-based vaccines present challenges that should be overcome prior to widespread use. A major
challenge is the immunosuppressive nature of TME´s, providing a barrier to effective anti-cancer
immune responses (Lee, et al., 2023). Another challenge is proper TAA selection while preventing
an autoimmune response. Lastly, a major hurdle remains in finding effective DC harvesting and
reimplantation methods.
3.2 Microbial-Based Vector Vaccines:
Microbial-based vector vaccines rely upon the principle of delivering tumor antigens using
microbes, such as viruses and bacteria, as vectors to activate MHC class I and II pathways,
providing a stronger immune response.
A category of viral-based vaccines employs genetic modification and engineering to produce
weakened (attenuated) viruses that introduce tumor antigens to immune cells. This will cause an
immune response against the expressed antigens, promoting the humoral and cellular immune
system to more easily identify and attack the targeted tumor cells. Another category of viral-based
vaccines, named oncolytic virotherapy, uses viruses with the ability to attach to tumor antigens, to
selectively infect and kill tumor cells.
Moreover, bacteria-based vaccines exploit the ability of bacteria to produce a large amount of
proteins through the implantation of genetically modified plasmids in the cytoplasm. The usage of
bacteria instead of viruses provides an advantage in that bacilli survive for longer and in more
hypoxic environments, making them able to thrive in the hypoxic TME.
3.3 Peptide-based Vaccines:
Since the human immune system can be sensitized against foreign immunogens, peptide-based
vaccines operate to induce immunity against specific tumor antigens and proteins. In this vaccine,
a short peptide chain (20-30 amino acids long) is injected to help CD8+ and CD4+ T-cells to target
tumor cells. These peptide chains are smaller than antigens and thus often appear to be less
immunogenic, sporadically failing to initiate a T-cell immune response. Although less
immunogenic, peptide-based vaccines are easier to synthesize, cheaper to produce, and are less-
labile than other vaccines types.
3.4 Nucleic Acid-Based vaccines:
DNA and RNA are nucleic acids used in the cellular biology to encode and produce proteins.
Nucleic acid-based vaccines introduce DNA or RNA into host cells, which in turn, express proteins
that are identified by the host immune system to counter cancer cells. Since DNA is more stable
and easier to produce than RNA, DNA vaccines were more vigorously studied and used in current
vaccination research. Nonetheless, recombinant RNA vaccines have shown excellent results after
the COVID-19 epidemic due to global research efforts.
DNA cancer vaccines are based on bacterial plasmids that encode one or several antigens, inducing
innate immunity activation and adaptive immune responses. DNA vaccine mechanisms are
classified into 3 categories:
1. Somatic cell DNA implantation, followed by direct antigen presentation to APC´s
2. Somatic cell DNA implantation, followed by antigen expulsion through secretion or apoptotic
bodies, leading to APC antigen identification
3. Antigen presenting cell DNA implantation with subsequent CD8+ and CD4+ T-cell activation
RNA vaccines utilize the same principles as DNA vaccines; however, direct mRNA implantation
bypasses DNA transcription, and thus are translated more readily in non-dividing cells. They are
simpler to employ since they do not require entry into the nucleus and are not incorporated into
cellular DNA. Some concerns regarding RNA vaccination stem from its innate immunogenicity
and pro-inflammatory properties. Furthermore, mRNA vaccines suffer from inhibited cellular
mRNA replication, stalled translation, and intracellular RNA degradation in sizable populations
(Liu, 2019).
Nucleic acid-based vaccines are less stable than other vaccine types due to the inherently sensitive
information they carry. Any modification to the injected DNA or RNA can render the vaccine
useless or cause long-lasting side effects. As a result, adjuvant and carrier selection are critical to
demonstrate vaccine efficacy. A suitable carrier is important to prevent DNA and RNA
degradation through enzymatic lysis, and since mRNA is negatively charged, a carrier is essential
for intracellular delivery. Lipid-based, polymer-based, peptide-based, or a viral vector are used as
carriers to ensure intact delivery (Zeng, et al., 2022).
3.5 Induced Pluripotent stem cell-based vaccines:
Induced Pluripotent stem cell-based vaccines (iPSCs) are a valuable emerging tool in personalized
medicine. Since they are derived the patient’s body, they eliminate the risk of immune rejection.
iPSCs are produced through the reprogramming of adult somatic stem cells into regressing into
the more primitive pluripotent form. Pluripotent stem cells possess the ability to differentiate into
different tissue, unlike mature somatic cells. Although iPSC production and research are still in
their early stages with inconsistent results, they are being used in current ongoing trials,
specifically to replace or generate damaged tissues (Bragança, et al., 2019). In the field of
immunotherapy, iPSCs are engineered to produce TME-associated proteins to illicit a humoral and
cellular immune response. Although iPSC use eliminates the risk of immune rejection, their
volatile non-mature nature raises the risk of teratoma formation after injection.
4. Limitations of Cancer Vaccines:
In spite of their innovative and promising potential, cancer vaccination still poses challenges that
hinder its ability to be an all-in-one treatment. The challenges pertain to the research landscape
and clinical considerations.
4.1 Research challenges:
The human immune system is very complex with many interacting and moving parts. Further, the
TME of different tumor types can be greatly heterozygous among species and even individuals.
These differences create large barrier that impedes the carry-over of animal research to human
trials. The use of humanized mice resembles only a primitive model of how the human immune
system functions. Humanized mice have less lymph nodes, underdeveloped immune cell
populations, and have proved difficult to simulate the human immune deficiency environment due
to their simplistic immune systems (Fan, et al., 2023). Moreover, TME heterozygosity makes
appropriate tumor antigen selection a formidable task. Our current medical technologies have not
yet reached a level where personalized vaccine production is effective, or even possible. Secondly,
ethical considerations regarding stem cell research are significant. Genetic modification or
embryonic stem cell harvesting required for iPSC research demand careful evaluation (Rafati, et
al., 2022).
4.2 Clinical Considerations:
Modern medical practices apply the principles of combination therapy in many medical fields and
is a cornerstone in oncology. Combination therapy incorporates more than one type of treatment
to improve patient outcomes and/or decrease the incidence of side-effects (Mokhtari, et al., 2017).
Radiotherapy, surgery, chemotherapy, immunotherapy, hormonal therapy, and nuclear medicine
are all used currently used in conjunction with one another in the treatment of different cancer
types. For example, in breast cancer, hormonal therapy and chemotherapy are commonly used to
reduce metastatic burden, and transform inoperable tumors into surgically resectable, improving
patient outcomes and survival (Burguin, et al., 2021). Another example is the use of radiotherapy,
nuclear medicine, and chemotherapy in the treatment of anaplastic thyroid tumors (Jannin, et al.,
2022).
Immunotherapy relies on the host immune system to provide effective resistance and treatment for
cancer; however, many combination therapy regimens cause immunodeficiency, in addition to the
immunosuppressive TME of most tumors. Cancers like leukemias and lymphomas
characteristically cause pancytopenia, leading to the loss of effective host immune responses
(Chandra, et al., 2022). Likewise, HIV, a cancer-causing virus, causes acquired human
immunodeficiency syndrome (AIDS).
Regarding microbe-based vaccines, pre-existing immunity limits their effectiveness in the
population. Further, the use of live or attenuated vaccines is contraindicated in immunodeficient
individuals, due to the risk of reactivation and infection. This is especially dangerous in cancer
patients requiring radiotherapy, nuclear therapy, or cytotoxic chemotherapy regimens (Kaczmarek,
et al., 2023).
5. Cancer Vaccine Future Prospects:
Although currently, cancer immunologic research has not yielded many positive results, many
advances and theories have emerged that will increase the quality and success of future cancer
vaccine research, including:
1. The identification of key TAAs for future research
2. Discovery of the key role T-cells play in anti-cancer immunology
3. Better understanding of T-cell activation and APC functioning
4. Better cancer vaccine adjunct understanding
5. Better measurement of cancer vaccine pharmacodynamics
6. Conclusion:
With advancing medical technology, previously devastating diseases have been overcome through
immunization and medicines. Nonetheless, cancer still remains to be a difficult hurdle to overcome
due to its diverse pathophysiology and variable treatment response. Many treatment modalities
have been shown to treat, or very rarely cure, cancer, but they still remain primitive in the face of
a developing world, where they carry significant mortality and morbidity. Cancer immunologic
treatment is a new frontier into a world where over-the-shelf medication and vaccines can be used
to prevent and treat cancer, while maintaining a relatively low risk of adverse events.
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