Vaccine Therapy for Non-Small Cell Lung Cancer

Yi Lyu

, Sutong Li

and Haoze Li

Shihezi University, Shihezi, Xinjiang, China

Wuhan University of Technology, Wuhan, China

High School Attached to Northeast Normal University International Curriculum Center, Jilin, China

Keywords: Non-Small Cell Lung Cancer (NSCLC), Cancer Vaccine, mRNA Vaccine.

Abstract: Lung cancer is a leading cause of cancer-related mortality, with non-small cell lung cancer (NSCLC)

being the most common and a major global health concern. While traditional treatments such as

radiotherapy, chemotherapy, and surgery have shown some effectiveness, challenges like tumor

heterogeneity, drug resistance, and significant side effects continue to result in poor prognosis and limited

survival improvement. In contrast, vaccine therapy presents a promising alternative, offering a favorable

safety profile, the potential for long-lasting immune responses, and the ability to reshape the tumor

microenvironment. This approach provides renewed hope for NSCLC patients. This review explores the

immune evasion mechanisms employed by NSCLC and discusses the principles, advantages, and progress

of various vaccine types, aiming to offer insights into the future development of vaccine-based treatment

strategies for NSCLC.

1 INTRODUCTION

In recent years, the global incidence and mortality

rates of cancer have continued to rise. According to

the 2024 cancer statistics, it is estimated that there

will be 226,650 new cases of lung cancer in the

United States, with approximately 124,730 deaths

(Siegel et al.,2015) Lung cancer remains the leading

cause of cancer-related deaths worldwide (18.7%)

(Bray et al.,2022), posing a significant public health

challenge. Lung cancer can be classified into non-

small cell lung cancer (NSCLC) and small cell lung

cancer (SCLC), with NSCLC accounting for about

85% of all lung cancer cases. NSCLC is further

divided into three subtypes: adenocarcinoma, large

cell carcinoma, and squamous cell carcinoma, with

adenocarcinoma being the most common type.

Among the risk factors for NSCLC, long-term

exposure to air pollution, prior radiation therapy to

the lungs, and family history are non-modifiable,

while smoking, radon exposure, and asbestos are

other important controllable risk factors. Due to the

lack of early diagnosis and the late onset of symptoms

during disease progression, the majority of NSCLC

patients are diagnosed at advanced or metastatic

stages, resulting in poor prognosis (Lahiri et

al.,2023). Currently, various treatment strategies such

as surgery, radiotherapy, chemotherapy, and even

targeted therapy are widely used for NSCLC

treatment. Although these methods have controlled

tumor progression to some extent, they are associated

with significant side effects (Xu et al.,2024),

including hair loss, organ toxicity, secondary tumors,

and drug resistance, and their therapeutic efficacy

remains limited. In this context, vaccine therapy, as

an innovative approach to activate specific anti-tumor

immune responses, has gradually become a cutting-

edge research direction in NSCLC treatment.

The core mechanism of vaccine therapy lies in

delivering tumor-associated antigens (TAAs) or

neoantigens to activate host antigen-presenting cells

(APCs), thereby initiating an immune response

mediated by cytotoxic T lymphocytes (CTLs) against

tumors (García-Pardo et al.,2022). Compared to

traditional immunotherapies, vaccine therapy offers

several advantages, such as enhanced

immunogenicity through epitope optimization and

the induction of long-term immune memory to

prevent tumor recurrence. Particularly when targeting

specific tumor antigens, vaccines can provide more

accurate immune responses, avoiding the side effects

of systemic immunity. With continuous optimization

in vaccine design, immunotherapy has demonstrated

great potential in improving patients' quality of life

and extending survival. Given these advantages,

vaccine therapy, as an emerging approach in cancer

treatment, has gradually gained clinical attention and

application. Therefore, this article aims to provide an

Lyu, Y., Li, S. and Li, H.

Vaccine Therapy for Non-Small Cell Lung Cancer.

DOI: 10.5220/0014488500004933

Paper published under CC license (CC BY-NC-ND 4.0)

In Proceedings of the 1st International Conference on Biomedical Engineering and Food Science (BEFS 2025), pages 345-351

ISBN: 978-989-758-789-4

345

overview of the current research progress in NSCLC

vaccine therapy, focusing on the principles,

mechanisms, and clinical potential of mRNA

vaccines, Oncolytic virus vaccines, and personalized

neoantigen vaccines in the treatment of NSCLC.

2 MECHANISMS OF IMMUNE

EVASION AND

IMMUNOTHERAPY IN NSCLC

In recent years, studies have found that although the

human immune system can generate specific anti-

tumor immune responses, many tumors can still

progressively grow and persist within the body,

evading attacks from the host's immune system or

preventing the body from mounting an effective

immune response, ultimately leading to the death of

the host. The tumor microenvironment (TME) is a

significant factor contributing to tumor immune

evasion. The TME consists of tumor parenchymal

cells, stromal cells, various immune cells, and a range

of membrane-bound or secreted bioactive substances,

such as VEGF. These components not only promote

the growth of surrounding blood vessels to supply

nutrients to the tumor but also directly act on tumor

cells (Zhao et al.,2022). Additionally, within the

tumor microenvironment, immunosuppressive cells

such as regulatory T cells (Tregs), tumor-associated

macrophages (TAMs), and myeloid-derived

suppressor cells (MDSCs) create an

immunosuppressive environment. These cells can

directly inhibit cytotoxic immune cells from attacking

cancer cells or indirectly release inhibitory factors

that downregulate immune cell function (Madeddu et

al., 2022). This results in tumor cells becoming

insensitive to immune responses, evading immune

surveillance, and continuing to grow or even

metastasize.

Currently, immune checkpoint inhibitors (ICIs)

such as PD-1/PD-L1 inhibitors are widely used in

clinical treatment. They aim to block the tumor's

suppression of immune cells to exert anti-tumor

activity. However, their efficacy is limited due to the

low response rates in advanced NSCLC patients and

the inherent and acquired resistance mechanisms of

tumor cells to ICIs. In contrast, vaccine therapy offers

potential advantages by targeting multiple antigenic

epitopes, reducing the likelihood of tumor resistance.

It can also broadly activate the host's immune defense

mechanisms and enhance the clearance of tumor

cells, demonstrating promising applications in

NSCLC treatment research (Mamdani et al., 2022).

3 MECHANISM AND

ADVANTAGES OF mRNA

VACCINES

mRNA vaccines innovatively activate the host's

adaptive immune response by delivering genetic

information encoding pathogen-specific antigens.

Their mechanism of action relies on the host cell's

natural protein synthesis system—the modified

mRNA carried by the vaccine is delivered to the

cytoplasm, where it directly utilizes the ribosome

translation system to produce the target antigen

protein. This "endogenous expression" strategy

breaks through the traditional exogenous antigen

delivery model of conventional vaccines, simulating

the natural infection process to achieve antigen

presentation. This approach not only stimulates the

production of neutralizing antibodies but also induces

T-cell immune responses. Notably, this technology

platform completely avoids the complex processes

required in traditional vaccine development, such as

pathogen amplification, culture, and antigen

purification, reducing the vaccine development cycle

from several years to a few weeks. This not only

provides a rapid response advantage in addressing

emerging infectious diseases but also holds

significant potential for rapidly evolving tumor

antigens (Wu et al.,2024). In terms of safety, mRNA

vaccines do not carry the potential risk of genomic

integration and do not require handling live

pathogens, thereby reducing biosafety concerns.

More importantly, mRNA vaccines can be flexibly

customized according to individual patient

differences. Particularly in tumor immunotherapy, if

timely updates to target new antigens are needed, the

design and preparation can be completed in the

shortest time possible. These advantages make

mRNA vaccines highly promising in both infectious

disease prevention and tumor immunotherapy.

To minimize the likelihood of inflammatory

responses caused by exogenous mRNA, lipid

nanoparticles (LNPs) are currently commonly used as

the mRNA delivery system. LNPs consist of four

main components: ionizable lipids, cholesterol,

helper phospholipids, and PEG-modified lipids.

These components work together to form a

sophisticated system that both protects mRNA and

efficiently delivers it to target cells. Ionizable lipids

(such as ALC-0315) are one of the core components

of LNPs. They remain neutral at physiological pH,

helping to reduce systemic toxicity, but become

protonated in the acidic endosomal environment,

facilitating the release of mRNA. Cholesterol acts as

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a structural stabilizer, enhancing the integrity of the

nanoparticles by modulating membrane fluidity.

Helper phospholipids (such as DSPC) promote the

formation of lipid bilayers, optimizing the assembly

process of the particles. PEG-modified lipids reduce

particle aggregation through steric hindrance and

regulate pharmacokinetic properties. This delivery

mechanism enables mRNA vaccines to achieve cell-

specific uptake through receptor-mediated

endocytosis. When LNPs enter target cells, the

ionizable lipids undergo conformational changes

triggered by the acidic endosomal environment,

interacting with endosomal membrane phospholipids

to facilitate the release of mRNA into the cytoplasm.

Subsequently, the mRNA is translated into antigen

proteins by ribosomes in the cytoplasm and presented

to T cells via MHC class I and II molecules, thereby

inducing robust humoral and cellular immune

responses.

4 mRNA VACCINES IN

CLINICAL TRIALS FOR

NSCLC TREATMENT

4.1 CCV9201 and CV9202 Vaccine

In the design of tumor-associated antigens, the

CV9201 vaccine encodes five TAAs: NY-ESO-1,

MAGE-C1, MAGE-C2, Survivin, and TPBG. The

CV9202 vaccine expands on CV9201 by including

six antigens (adding 5T4 and MUC1). CV9201

Vaccine: In a Phase I/IIa clinical trial involving 46

patients with advanced NSCLC, CV9201

successfully induced multiple antigen-specific

immune responses, including T-cell activation and

antibody production (Lang et al., 2022). Vaccine: In

a Phase Ib trial involving 26 patients with stage IV

NSCLC, antigen-specific immune responses were

detected, supporting its immune activation potential.

Both trials demonstrated good tolerability with no

serious adverse events reported, although significant

tumor regression was not observed, necessitating

further clinical validation. Notably, in the CV9201

trial, when combined with local radiotherapy, six

patients showed local tumor regression, and the

frequency of antigen-specific T cells in peripheral

blood increased 4-8 times. Preliminary data from the

CV9202 trial combined with anti-CTLA-4 therapy

showed a disease control rate (DCR) of 54%, though

larger sample sizes are needed for validation

(Sebastian et al., 2022).

4.2 RO7198457 Vaccine

The RO7198457 vaccine is a personalized

neoantigen-specific immunotherapy (Individualized

Neoantigen-Specific Immunotherapy, iNeST) based

on RNA-lipoplex (RNA-Lipo) technology, targeting

up to 20 patient-specific neoantigens. In patients with

metastatic solid tumors, this vaccine has

demonstrated a manageable toxicity profile (Zhang et

al., 2020) ， Additionally, it can induce robust

neoantigen-specific T-cell responses, with increased

T-cell infiltration observed in the tumor

microenvironment in some patients. Currently, a

Phase II trial combining RO7198457 with PD-1/PD-

L1 inhibitors is underway, aiming to overcome the

immunosuppressive tumor microenvironment and

further enhance clinical efficacy.

4.3 KRAS and ALK Driver Gene

Vaccines

Neoantigens derived from KRAS mutations are

highly immunogenic, but their efficacy requires

overcoming the suppressive tumor microenvironment

(Voena et al., 2015). Currently, clinical trials

(NCT05202561, NCT05254184) are exploring the

therapeutic potential of KRAS vaccines in

combination with immune checkpoint inhibitors. The

ALK rearrangement vaccine is a DNA vaccine

targeting the intracellular domain of ALK. In mouse

models, it has demonstrated the ability to induce

tumor-specific cytotoxic responses. Although still in

the preparatory Phase I stage, if its safety and

immunogenicity are confirmed, its combination with

other immunotherapies could provide new treatment

options for ALK-positive NSCLC patients (Sankar et

al., 2021; Kim et al., 2021).

5 mRNA VACCINES IN

CLINICAL TRIALS FOR

NSCLC TREATMENT

5.1 Principles and Types of Oncolytic

Viruses

With continuous in-depth research into the

mechanisms of virus-host interactions, viruses have

emerged as a promising tool for cancer treatment.

Oncolytic viruses (OVs) primarily refer to naturally

occurring or genetically modified viruses that can

selectively infect and lyse tumor cells while inducing

immune responses. Currently, common oncolytic

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viruses are mainly divided into two types: DNA

viruses (such as the herpes simplex virus T-VEC, the

only FDA-approved oncolytic virus) (Conry et al.,

2018) and RNA viruses (such as measles virus and

reovirus). DNA viruses, due to their larger genomes,

can carry more exogenous genes or undergo genetic

editing, thereby enhancing therapeutic activity.

Additionally, compared to RNA viruses, DNA

viruses have more stable genomes with lower

mutation rates, making them suitable for long-term

treatment. Beyond the aforementioned viruses,

various other types of viruses are under clinical

investigation to elucidate their therapeutic efficacy

and safety in humans (Macedo et al., 2020).

5.2 The Role of Oncolytic Viruses in

Immunotherapy

Oncolytic viruses (OVs) play a significant role in

cancer treatment, primarily through direct oncolytic

effects and induction and enhancement of anti-tumor

immune responses (Ma et al., 2023). Direct oncolysis

is the initial process in the treatment, where the tumor

selectivity of oncolytic viruses is enhanced by

modifying certain protein structures, allowing them to

bind to virus-specific receptors on the tumor surface

and enter the cells. Due to the inactivation of the p53

pathway and defects in the interferon (IFN) signaling

pathway in tumor cells (Xu et al.,2024,Hemminki et

al.,2020)，an effective antiviral response cannot be

initiated, leading to unrestricted viral replication.

After the tumor cells are lysed, the released progeny

viruses continue to infect neighboring tumor cells,

creating an "oncolytic cascade effect."

Simultaneously, damaged tumor cells release

damage-associated molecular patterns (DAMPs) and

tumor-associated antigens (TAAs). These signaling

molecules are captured and presented by antigen-

presenting cells (such as DCs) to CD8+ T cells,

thereby initiating a specific immune response.

Notably, the tumor microenvironment (TME)

provides ample conditions for tumor proliferation,

differentiation, and metastasis. Due to the presence of

a large number of inhibitory cells and cytokines,

tumors are not sensitive to the body's immune cells

and exhibit weak immune systems. However, the

PAMPs, DAMPs, and TAAs released by oncolytic

virus (OV)-mediated tumor cell lysis can recruit

various immune cells such as NK cells, macrophages,

and neutrophils, thereby reversing the tumor

microenvironment(Melcher et al.,2021). One study

reported that Coxsackievirus B5/Faulkner (CV-B5/F)

demonstrated potential oncolytic effects in a non-

small cell lung cancer (NSCLC) animal model by

inducing apoptosis and autophagy (Cui et al., 2023).

In addition to direct oncolysis, CV-B5/F can also

induce a systemic anti-tumor response and recruit

specific T cell infiltration. For refractory NSCLC

cells, the combination of CV-B5/F with DNA-

dependent protein kinase (DNA-PK) or ataxia-

telangiectasia mutated (ATM) inhibitors significantly

enhances the oncolytic effect.

5.3 Combination of Oncolytic Virus

Vaccines with Other Therapies

Given that oncolytic viruses possess dual effects—

direct oncolysis and enhanced immune response, as

well as the ability to improve the tumor

microenvironment—combining oncolytic viruses

with other immunotherapeutic methods may

significantly enhance treatment efficacy. Chimeric

antigen receptor (CAR)-T cell therapy, as a

revolutionary treatment strategy, has made

remarkable progress in anti-tumor therapy. However,

the dense stroma of solid tumors (such as collagen

deposition and fibrosis), abnormal vascular

structures, and immunosuppressive factors in the

tumor microenvironment hinder the infiltration and

function of CAR-T cells. Oncolytic viruses can

disrupt tumor tissue, reduce stromal density, and

provide physical pathways for CAR-T cells.

Additionally, by inducing the release of pro-

inflammatory factors (such as IL-2 and IL-12) and

reversing immunosuppressive signals in the tumor

microenvironment, oncolytic viruses can directly

activate CAR-T cells, enhancing their proliferation

and effector capabilities (Hemminki et al., 2020).

6 PERSONALIZED

NEOANTIGEN VACCINES

The goal of innovative cancer vaccines targeting

novel antigens is to induce highly specific immune

responses while minimizing autoimmune risks. Next-

generation sequencing technologies have enabled

researchers to systematically examine how

neoantigen peptides activate CD8+ T cells and to

uncover significant increases in CD4+ T cell and NK

cell proliferation. These insights deepen our

understanding of the complex mechanisms

underlying antitumor immune responses and

underscore their potential biomedical applications.

Notably, the binding affinity of a neoantigen to MHC

molecules, alongside the diversity of HLA genotypes,

is crucial for identifying immunogenic targets.

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Evidence suggests that only a small fraction of

somatic mutations predicted through mutational

spectrum analysis ultimately function as

immunogenic neoantigens. This finding highlights

new possibilities for optimizing the efficacy and

efficiency of multi-peptide cancer vaccines.

Unbiased whole-genome or whole-exome

sequencing provides an irreplaceable foundation for

identifying promising neoantigens by revealing the

complete “epitope landscape.” Moreover, messenger

RNA (mRNA) technology offers a highly adaptable

platform with a relatively short development cycle for

producing therapeutic cancer vaccines. As a versatile

antigen-delivery vector, mRNA excels in designing

vaccines that target unique tumor-specific mutations.

Such personalized designs allow for the induction of

potent immune responses that can precisely eliminate

malignant cells while sparing healthy tissues,

potentially improving therapeutic outcomes.

7 FUTURE DEVELOPMENT AND

CHALLENGES

7.1 Establishment of Animal Models of

HIV Infection

Establishing cross-species animal models for HIV

infection is essential for advancing our understanding

of HIV/AIDS pathogenesis. However, HIV-1 is

species-specific and only infects humans and a few

non-human primates, making it challenging to study

in traditional animal models such as mice. A recent

study successfully created a mouse model capable of

being infected with HIV-1. By introducing the CD4,

CCR5, and CyclinT1 genes into the mouse leukemia

cell line L1210 using lentiviral vectors, the

researchers enabled these cells to express the

necessary receptors and co-receptors for HIV

infection. Fluorescence analysis and sequencing

confirmed the significant expression of CD4, CCR5,

and CyclinT1 proteins in the transgenic cells, and

HIV-1 RNA was detected in the culture medium,

indicating successful virus entry and replication. This

model provides a critical platform for studying HIV-

1 cross-species infection and offers new directions for

HIV vaccine development, antiviral drug screening,

and further exploration of HIV/AIDS pathogenesis

(Karuppusamy et al., 2021).

7.2 Cases of AIDS Cure

The "Berlin Patient," Timothy Ray Brown, became

the first person in the world to be cured of AIDS

following a bone marrow transplant in 2007. Brown,

who was also battling leukemia, received a transplant

from a donor with the CCR5Δ32 mutation, which

naturally blocks HIV entry into cells. After the

procedure, not only was Brown’s leukemia

successfully treated, but HIV was undetectable in his

body, effectively achieving a "double cure."

Similarly, the "London Patient," Adam Castillejo,

underwent a hematopoietic stem cell transplant for

Hodgkin's lymphoma in 2016, receiving cells with the

CCR5Δ32 mutation. After discontinuing

antiretroviral therapy, HIV remained undetectable in

his body for several years, with no recurrence of the

infection.

These two groundbreaking cases highlight the

potential of CCR5 gene modification for both

controlling and potentially curing HIV. However, the

procedures involved—particularly bone marrow

transplants—are highly complex, risky, and prone to

serious complications. Moreover, finding matching

donors is exceedingly difficult, limiting the

widespread applicability of this treatment. While

these cases offer hope and insight for CCR5 gene

editing in HIV treatment, they remain exceptional

cases and do not yet represent a practical, widely

accessible solution. Nonetheless, they provide

invaluable direction for ongoing research into CCR5

gene editing and its potential to prevent or cure HIV

infection.

7.3 Safety and Drug Resistance Issues

The clinical translation of vaccine therapies requires

a delicate balance between immune activation effects

and safety risks. For example, mRNA vaccines,

which rely on lipid nanoparticle (LNP) delivery

systems, may cause transient inflammatory reactions,

typically manifesting as fever or localized tissue

redness. The use of oncolytic virus vectors requires

vigilance against potential systemic diffusion-related

toxicity. Additionally, repeated immune stimulation

may lead to functional exhaustion of antigen-specific

T cells, characterized by upregulation of immune

checkpoint molecule co-expression, thereby

weakening the persistence of immune responses. In

terms of tumor resistance, epigenetic silencing of

target antigens or reprogramming of the

immunosuppressive microenvironment are the main

mechanisms of immune escape. The former involves

the loss of key antigen presentation components (such

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349

as MHC complex subunits), while the latter is

associated with abnormal activation of

immunosuppressive factor networks. To overcome

these limitations, studies have shown that combining

epigenetic modulators with vaccines can

synergistically reshape the immune

microenvironment, and multi-antigen targeting

designs can reduce the probability of clonal escape.

In the future, integrating high-resolution molecular

mapping technologies (such as single-cell

sequencing) with dynamic vaccine design platforms

is expected to enable real-time tracking and precise

intervention in tumor adaptive evolution pathways.

8 CONCLUSION

In conclusion, non-small cell lung cancer (NSCLC)

remains a leading global health concern, with existing

therapies—such as surgery, radiotherapy, and

chemotherapy—facing significant limitations due to

tumor heterogeneity, drug resistance, and adverse

effects. Vaccine-based strategies, including mRNA

platforms, demonstrate considerable promise in

eliciting robust antitumor immune responses and

reshaping the tumor microenvironment. Clinical

studies on vaccines such as CV901, CV90,

RO7198457, and those targeting KRAS or ALK

mutations indicate that these approaches can induce

detectable immune responses and confer certain

therapeutic benefits; however, additional research is

required to achieve more pronounced tumor

regression. Efforts to optimize vaccine efficacy

highlight the potential of combined approaches—for

example, the co-administration of mRNA vaccines

with oncolytic viruses and the development of

bispecific vaccines. Although timely manufacturing

poses logistical challenges, integrating genomic and

multi-omics data into vaccine design can enable the

rapid development of personalized and precise

immunotherapies for NSCLC. Moreover, strategies

involving epigenetic regulation, multi-antigen

targeting, and high-resolution molecular profiling

hold promise in mitigating safety risks and drug

resistance. Ultimately, harnessing these advances

may transform current treatment paradigms for

NSCLC and spark innovative applications in the

clinical arena. Nevertheless, several hurdles remain

for neoantigen-based therapies, including the

accurate prediction of immunogenicity and the

optimization of in vivo transfection efficiency.

Overcoming these challenges is crucial for realizing

the full therapeutic potential of vaccine-based

strategies for NSCLC.

AUTHORS CONTRIBUTION

All the authors contributed equally and their names

were listed in alphabetical order.

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