


































Glioblastoma Body.docx


Berkeley
Pharma Tech
Journal of Medicine

Correspondence: 
Daniyalatiq7@gmail.com

Keywords:
Neoantigen
Glioblastoma
Monoclonal Antibodies 
Immune Checkpoint Inhibitors 
Personalized Therapy

Submitted: May 8, 2023 
Accepted: July 14, 2023 
Published: December 30, 2023

Full Open Access

Creative Commons Attribution 
License 4.0

Exploring Novel Neoantigen-Based 
Treatment Methods for 
Glioblastoma
By: Daniyal Atiq, Yacoub Alokam, and Suraj Shah

Abstract
Glioblastoma, constituting almost half of all malignant brain tumors, presents a 
formidable challenge in treatment due to the blood-brain barrier's protective role 
against certain therapies. These tumors, characterized by rapid growth, tissue 
invasion, and diverse evolving cells, afflict individuals of all ages and resist 
conventional cancer treatments despite extensive biomedical research. An innovative 
approach to glioblastoma treatment involves leveraging neoantigens, specific to cancer 
cells and targetable by the immune system. Clinical trials suggest that neoantigen-
based treatments hold promise, offering more effective and personalized options for 
patients. Exploring this avenue, including vaccines, immune checkpoint blockers, and 
adoptive cellular therapies, is crucial for improving outcomes. This paper reviews 
novel therapeutic options within neoantigen-based treatments, providing insights into 
potential advancements against glioblastoma.



1. Introduction

The aim of this paper is to explore and evaluate the e�cacy of
neoantigen-based vaccines, immune checkpoint blockers, and adoptive
cellular therapies as potential treatment methods for Glioblastoma. By
referencing scienti�c literature and clinical trials, this research seeks to
accomplish the following objectives:

1.1. Reviewing the History and Background of Glioblastoma Treatment:

- Conduct a comprehensive analysis of the historical context and
background of glioblastoma treatment methods utilizing
scienti�c databases such as PubMed, Google Scholar,
CINAHL, etcetera.

- Highlight the limitations and challenges associated with
conventional treatment approaches, such as surgery, radiation
therapy, and chemotherapy.

1.2. Investigating Neoantigens as Potential Treatment Options for
Glioblastoma:

- Review scienti�c literature to examine the role of neoantigens in
glioblastoma immunotherapy.

- Explore the mechanisms through which neoantigens can elicit
an immune response against glioblastoma tumor cells.

- Evaluate the e�cacy and safety of neoantigen-based vaccines in
preclinical and clinical settings.

1.3. Assessing the E�cacy of Immune Checkpoint Blockers in
Glioblastoma Treatment:

- Examine the role of immune checkpoint blockers, such as
PD-1/PD-L1 inhibitors and CTLA-4 inhibitors, in modulating
the immune response against glioblastoma.

- Analyze the outcomes of clinical trials and real-world evidence
regarding the use of immune checkpoint blockers in
glioblastoma patients.

- Assess the potential of combination therapies involving
immune checkpoint blockers and other treatment modalities.

1.4. Exploring Adoptive Cellular Therapies for Glioblastoma:

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- Investigate the use of adoptive cellular therapies, including
chimeric antigen receptor (CAR) T-cell therapy and
tumor-in�ltrating lymphocyte (TIL) therapy, in glioblastoma
treatment.

- Analyze the e�cacy and safety pro�les of adoptive cellular
therapies in glioblastoma patients.

- Evaluate the potential of enhancing the e�ectiveness of adoptive
cellular therapies through genetic engineering and personalized
medicine approaches.

By addressing these objectives, this article aims to contribute to the
advancement of glioblastoma treatment by shedding light onto the
potential of neoantigen-based vaccines, immune checkpoint blockers, and
adoptive cellular therapies as innovative and promising therapeutic
strategies.

2. Glioblastoma Background

Every year, it’s estimated that approximately 10,000 people will be
diagnosed with glioblastoma, which yields a 25% one-year survival rate as
well as a 6.8% 5-year survival rate.1 On average, patients survive eight months
before succumbing. Glioblastoma is a Grade IV brain tumor2—signifying
that the cells are actively dividing, and the tumor has dead tissue as well as
abnormal blood vessel growth—that stems from malfunctioning astrocytes,
glial cells that provide structural support to neurons, modulate synaptic
activity, and act as a major component in the blood-brain barrier.3

Figure 1. Glioblastoma Statistics

The age-adjusted incidence of glioblastoma has a positive correlation with
age, being 0.15 per 100,000 in children to 15.03 per 100,000 in patients

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between 75 and 84 years of age.4 Glioblastoma develops most commonly in
the frontal lobe, but has appeared in the temporal, parietal, and occipital
lobes, and could even grow into surrounding brain tissues.5 Common
symptoms of glioblastoma include seizures, coordination issues, paralysis,
fatigue, severe headaches, and cognitive impairment. Major risk factors have
yet to be identi�ed; however, it was recently discovered that exposure to
high ionizing radiation is a major contributor towards glioblastoma
development. Moreover, exposure to vinyl chloride, pesticides, smoking,
petroleum re�ning, and synthetic rubber have shown occasional positive
association with glioblastoma emergence.6 Currently, the main treatment
methods used include surgical resection, alkylating chemotherapy, radiation
therapy, and Tumor Treating Fields.6

The majority of gliomas have been found to contain point mutations in
isocitrate dehydrogenase 1 and 2. In Glioblastoma, molecular alterations
that have been discovered include mutations in genes regulating receptor
tyrosine kinase (RTK), rat sarcoma (RAS), phosphoinositide 3-kinase
(PI3K), p53, and retinoblastoma protein (RB) signaling.7 Current research
shows mutations in EGFR (57% of GBM patients), HER2, PDGFRA
(13%), c-MET (1.6%), FGFR (3.2%), PTEN (41%), and VEGFR genes are
therapeutic targets due to having shown ampli�cations or mutations from
dysregulated cell signaling cascades in glioblastoma.7

Kinase inhibitors haven’t proven to be e�ective in glioblastoma therapy due
to their low e�cacy in penetrating the blood-brain barrier; however, a
multitude of experimental treatments have emerged and shown consistent
progress. AZD3579 (EGFR inhibitor) has shown e�ective blood-brain
barrier penetration in vivo in rats and monkeys, however its safety and
e�cacy in humans has yet to be tested. Epitinib (EGFR inhibitor) was
reported to have optimal BBB penetration, is well-tolerated in patients, and
is e�ective in treating brain metastases as well. WSD0922 (EGFR inhibitor)
is reported to have high BBB penetration, reasonable safety, and has shown
antitumor properties in Glioblastoma PDX models.7

Tucatinib (HER2 inhibitor) can cross the blood-brain barrier and create
survival bene�ts in mice. For patients with breast cancer and brain

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metastasis, tucatinib produced better progression-free survival and overall
survival. Neratinib (HER2 inhibitor)had limited BBB penetration in mice
and was not successful in a phase II trial for patients that had
HER2-positive brain metastases.7

Additionally, for newly diagnosed Glioblastoma cases, clinical trials
involving the drug temozolomide—a monofunctional DNA alkylating
agent—have shown signi�cant progress. Adding the temozolomide regimen
improved the overall survival and progression free survival in patients with
GBM compared with radiotherapy alone. Temozolomide is a lipophilic
molecule that crosses the blood-brain barrier and is stable at the acidic pH
of the stomach and is therefore administered orally.7 Temozolomide is
currently being tested, in a phase II interventional clinical trial led by Wen et
al. (NCT02977780) via combination therapy with Neratinib, to study
overall survival compared to standard treatment in Glioblastoma patients.8

3. Neoantigen Background

Neoantigens are a class of proteins that arise in cancer cells with the
mutation of tumor DNA. The �rst discovery of neoantigens was made in
1988 by De Plaen and his colleagues.9 By utilizing cDNA library screening
on a mouse tumor model, they observed a single nucleotide di�erence
between the normal and tumor gene, resulting in a noticeable amino acid
change. This novel �nding led to the coining of the term “neoantigen”
which was used in further studies on human tumors including melanoma
and renal cell carcinoma.9

Neoantigens have proven e�cient immunogenic targets because of their
localization to cancer patients. The mechanism of action by which they
form explains the tumor-speci�city of neoantigens and their associated
potency in developing cancer treatment. First, mutations in tumor DNA
cause rise of new and mutated proteins in tumor cells. After completion of
function, these proteins are proteolyzed by the proteasome and the
degraded peptides are sent to the endoplasmic reticulum via a transporter
associated with antigen processing (TAP)protein.10 The protein-peptide
complex is then sent to the Golgi apparatus and then exported to the plasma
membrane with chaperone proteins. There, the major histocompatibility

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complex (MHC) displays protein fragments (post-proteolysis) to the
immune system to �ght infection by pathogens.
Neoantigens are a class of proteins that arise in cancer cells with the
mutation of tumor DNA. The �rst discovery of neoantigens was made in
1988 by De Plaen and his colleagues.9 By utilizing cDNA library screening
on a mouse tumor model, they observed a single nucleotide di�erence
between the normal and tumor gene, resulting in a noticeable amino acid
change. This novel �nding led to the coining of the term “neoantigen”
which was used in further studies on human tumors including melanoma
and renal cell carcinoma.9

Neoantigens have proven e�cient immunogenic targets because of their
localization to cancer patients. The mechanism of action by which they
form explains the tumor-speci�city of neoantigens and their associated
potency in developing cancer treatment. First, mutations in tumor DNA
cause rise of new and mutated proteins in tumor cells. After completion of
function, these proteins are proteolyzed by the proteasome and the
degraded peptides are sent to the endoplasmic reticulum via a transporter
associated with antigen processing (TAP) protein.10 The protein-peptide
complex is then sent to the Golgi apparatus and then exported to the plasma
membrane with chaperone proteins. There, the major histocompatibility
complex (MHC) displays protein fragments (post-proteolysis) to the
immune system to �ght infection by pathogens.

Figure 2. Mechanism of action of neoantigens

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In humans, the MHC is referred to as human leukocyte antigens (HLA),
which are encoded by genes on chromosome 6.11 HLAs work with T cells to
identify 'self' and 'foreign' cells and tissues in the body by displaying short
polypeptides to T-cell receptors. These polypeptides can be recognized as
‘foreign’ by tumor-in�ltrating lymphocytes (TILs) which results in the
activation of strong tumor-speci�c immune responses.12 There are two main
groups of MHC molecules, which bind to di�erent peptide sequences and
are recognized by separate T-cell types. MHC-class I genes consist of
HLA-A, HLA-B and HLA-C, and their attached peptides are recognized by
CD8+ T-cells.11 MHC-class II genes, on the other hand, consist of
HLA-DR, HLA-DQ and HLA-DP, and attached peptides are recognized
by CD4+ T-cells.11

Figure 3. Role of the Major Histocompatibility Complex (MHC)

Neoantigens are commonly confused with other tumor antigens that exist,of
which there are three di�erent classi�cations that T-cells can target.11Tumor-
associated (TAA) antigens are a group of proteins characterizedby
overexpression in cancer cells compared to normal tissue. They consist of
differentiation antigens, which are normal proteins that are increasingly
expressed due to uncontrolled division of cells that have speci�c functions
[eg. prostate-speci�c antigen (PSA) in prostate cancer.13 The other class is
overexpressed antigens, which are proteins that are greatly expressed due to
mutated genes characteristic of cancer [eg. Hepsin in prostate cancer].14 A
complete library of tumor-associated antigens can be found in the Cancer
Antigenic Peptide Database: https://caped.icp.ucl.ac.be/Peptide/list.
Cancer testis (CT) antigens are a family of TAA that are strictly found on
the testis and placenta. Due to their expression speci�city in the germ cells,
CT antigens found in other regions of the body indicate oncogenic causes.

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https://caped.icp.ucl.ac.be/Peptide/list


Hence, CT antigens are considered promising therapeutic targets. There is
also the fact that the testis do not express MHC-class I, therefore CT
antigens are recognized as ‘non-self.’ A comprehensive list of CT antigens
can be found in the CTDatabase: http://www.cta.lncc.br/. Finally, viral 
antigens are a family of TAA that are caused by a viral infection. Examples
include the human papillomavirus (HPV)which can cause cervical and
several other cancers, as well as hepatitis C which may lead to liver cancer
and non-Hodgkin's lymphoma. Neoantigens are unique to the
aforementioned antigen types because they arise from the onset of cancer,
thus it is the genomic mutations from the cancer that lead to the rise of new
(neo-)antigens in the body.14

In exploring neoantigen-based treatment, there is the distinction to be made
between public and private neoantigens. Public (shared)neoantigens are
common across cancer patients and typically occur in driver oncogenes and
tumor suppressor genes. Private (personalized)neoantigens are unique to
each patient and therefore require individualized treatment.

4. Potential Treatment Methods

4.1  Neoantigen-based Vaccines

The process of creating a neoantigen vaccine typically involves sequencing
the patient's tumor cells to identify the unique neoantigens present. Once
these neoantigens are identi�ed, they can be used to create a personalized
vaccine that is tailored to the patient's speci�c cancer. The goal of the
vaccine is to prime the immune system to recognize and attack the cancer
cells that display these neoantigens. This approach has the potential to be
more e�ective than traditional cancer treatments because it targets the
cancer cells directly while sparing normal cells.

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http://www.cta.lncc.br/


Figure 4. Mechanism of Action for Protein-peptide vaccine

4.2  Protein-Peptide Vaccines

Protein peptide vaccines contain speci�c antigens which are immunogenic
and unique to the patient's tumor, with potential immunomodulating and
antineoplastic activities.15 Upon vaccination, with the neoantigen peptide
vaccine, the peptides stimulate the host’s immune system to elicit a speci�c
cytotoxic T-lymphocyte (CTL)response against the tumor cells that are
expressing the targeted neoantigens, thereby resulting in tumor cell lysis.

According to the FDA, with respect to the mechanism of action,
neoantigen-based protein-peptide vaccines use short peptide fragments to
induce highly targeted immune responses while simultaneously avoiding
allergic responses. Peptide epitopes can bind antibodies in three
conformations: alpha-helical, beta-strand/extended, or loop. Since the
peptide epitope’s spatial conformation among the antigen-antibody
complex is signi�cant, vaccines must be engineered in a conformationally
correct way to produce optimal results. To constrain peptide epitopes when
epitope conformation is important, some methods utilized include covalent
side chain-side chain cross linking and integration into a larger sca�old.
Emulsions, which act as delivery systems for various peptides, form a depot
at the site of injection that attracts immune cells.16 The presence of antigen
depots at organs releasing low-level antigens induces a strong immune
response and promotes tolerance. The stability of these emulsions as
delivery systems plays a key role in vaccine safety and e�cacy.16

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The process of developing a neoantigen-based peptide vaccine starts with
extracting a sample of peripheral blood.17 Peripheral blood mononuclear
cells (PBMCs) are then isolated from the blood sample, and subsequently
are di�erentiated into dendritic cells—the antigen presenting cells.
Simultaneously, the peripheral blood sample and a tumor sample are run
through Sequencing and Computational Neoantigen Identi�cation:
whole-genome sequencing (WGS), whole-exome sequencing (WES), and
next-generation sequencing (NGS).18 The identi�ed neoantigens are
validated in vitro via ELISpot, MHC tetramer, and tumor organoids, which
have shown in studies to retain the neoantigen features of parental tumors.
Then, the selected neoantigens are loaded onto dendritic cells and integrated
into peptide vaccines for treatment.17

WGS, one of the previous sequencing identi�cation methods, determines
the order of the nucleotides in the individual’s DNA, however its
production of complex datasets that require bioinformatics expertise makes
it ine�cient timewise. WES utilizes probes and hybridization to analyze the
exome, which despite only constituting 1-5% of the genome, contains
approximately 85% of disease-related variants. WGS is more time-e�cient
and allows for greater sequencing capabilities. NGS, re�ective of WGS, is
used to determine nucleotide sequences in targeted regions of DNA and is
capable of sequencing an entire human genome within one day.19 It’s
evident that with these three sequencing methods, identifying neoantigens
and somatic mutations would be carried out e�ciently with regards to time
and costs.

In two clinical trials reported by Hilf et al. (30568303) and Keskin et al.
(30568305) in 2019, neoantigen-peptide vaccines produced somewhat
successful therapeutic results for glioblastoma.20,21 In Hilf et al.’s trial,
�fteen patients, all of whom were recently diagnosed with glioblastoma,
were found to possess the human leukocyte antigen (HLA)-A*-2:01 or
HLA-A*24:02. In APVAC1 (actively personalized vaccine 1), patients
received a vaccine that targeted unmutated antigens, and in APVAC2, the
vaccine targeted neoantigens. Compared to classic treatment, patients who
received APVAC1 and APVAC2 had an increase in median overall survival
of 29 months, and an increase in median progression-free survival of 14.2

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months. In the tumor, the vaccine injection induced T-cell expansion;
however, at the vaccine’s injection site, nearly all patients experienced some
form of disease.20 In a trial led by Keskin et al., ten patients with newly
diagnosed glioblastoma were treated with the personalized neoantigen-based
vaccine after being treated surgically and with radiotherapy. Though some
experienced an increase in CD8+ T cells in the environment of recurrent
tumors, as well as a small increase of PD-1+ tumor in�ltrating CD8+ T
cells, all of the patients ended up dying as a result of disease progression,
with an average survival of 16.8 months and progression-free survival of 7.6
months.21

Reardon et al. (NCT02287428) is conducting an ongoing phase I
interventional clinical trial studying the neoantigen-speci�c peptide vaccine
NeoVax, alongside the monoclonal antibody Pembrolizumab, radiation
therapy, and Temozolomide in subjects with glioblastoma.22 The clinical
trial involves �ve cohorts, each receiving either separate individual or
combinations of treatments. The �rst cohort receives NeoVax and radiation
therapy, the second starts pembrolizumab within two weeks of the start of
radiation therapy and continues triweekly for two years, the third starts
pembrolizumab about three weeks after completion of NeoVax priming and
continues triweekly for two years, the fourth receives a single dose of
pembrolizumab two weeks after the start of radiation therapy and restarts
concurrently three weeks after completing NeoVax priming, and the �fth
enrolls patients with tumors for which the MGMT status is (partially)
methylated and receives standard temozolomide with radiation and
adjuvantly for six cycles after radiation therapy. The primary outcomes are
the number of participants with adverse events to determine the tolerability
and safety (all cohorts), the number of participants with at least ten
actionable peptides to measure the feasibility of the study (cohort 1), and
the number of participants able to initiate vaccine therapy after radiation
therapy within 12 weeks of the date of surgery (cohort 1). The secondary
outcomes are the number of participants who experience IFN-γ T-cell
responses at week 16 (all cohorts), the number of participants who are alive
and don’t demonstrate glioblastoma progression eight months after
resective surgery (cohorts 1, 1a, 1b, 1c), and the number of participants who
are alive without having glioblastoma progression eleven months after

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resective surgery (cohort 1d).22 As the study is ongoing, �nal results and data
have not been collected yet.

4.3  Nucleic acid (DNA and mRNA vaccines)

Nucleic acid vaccines are another category of treatment methods available
for cancer patients, of which there are two types: deoxyribonucleic acid
(DNA) and messenger ribonucleic acid (mRNA) vaccines.23 For DNA
vaccines, a bacterial plasmid is used as a vector to introduce a gene encoding
antigens. The plasmids then replicate, and by using antibiotics, the vectors
exhibiting antibiotic resistance can be separated. DNA vaccines are able to
activate both humoral and cellular immune responses, and they can be
delivered intramuscularly (IM), intradermally (ID), mucosally, and/or
transdermally. The process by which genomic alterations occur include
internalization of the DNA vaccine into the cell, transcription of the
genomic information at the nucleus, and translation of that info within the
cytoplasm.24 This ultimately leads to expression of proteins in vaccinated
hosts, however there are three distinct mechanisms by which these proteins
reach the T-cells for recognition and targeting. One way includes the use of
MHC I complexes in somatic cells, which presents proteins to CD8+ T
cells. Another method uses professional antigen presenting cells (APCs),
like dendritic cells (DCs),that are transfected with plasmid DNA and then
present antigens to T cells through MHC I or II complexes. A third way
involves the phagocytosis of plasmid-transfected somatic cells by APCs,
resulting in the cross priming and presentation of antigens to both CD4+
and CD8+ T cells.23

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Figure 5. Molecular mechanism of DNA vaccines

There are several current clinical trials experimenting with the use of DNA
vaccines in patients with glioblastoma. In Johanns et al, the initiative is to
evaluate the safety, feasibility, and immunogenicity of a personalized
neoantigen-based vaccine in subjects with newly diagnosed, unmethylated
glioblastoma.25 In this trial, patients will each receive standard radiation
therapy as well as administered neoantigen DNA vaccines using the
CELLECTRA®2000 EP Device. The vaccine used is a combination of
GNOS-PV01 + INO-9012, DNA vaccines which have previously shown
immunogenicity in newly diagnosed GBM patients when administered
alongside Libtayo, radiation, and temozolomide. Safety of the vaccine will
be determined by dose-limiting toxicities, as per the Common Terminology
Criteria for Adverse Events Version 5.0 (CTCAE v5) published by the U.S.
Department of Health and Human Services (USDHHS). Alongside safety,
feasibility of this DNA vaccine is also being considered, for which there are
three necessary conditions: e�ciency of vaccine manufacturing,
administration, and ability of the vaccine to identify neoantigens in the
patient. Additionally, the immunogenicity of the vaccine will be determined
by percentage of neoantigens that elicit a neoantigen-speci�c T cell
response, as well as the associated CD8 T-cell response, and overall survival
rate.25

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Some clinical trials are testing the use of DNA vaccines in combination with
other immunotherapies to achieve a higher magnitude and breadth of
neoantigen-speci�c T cell responses. In another trial by Johanns et al, a
personalized neoantigen vaccine is being used concurrently with
Retifanlimab PD-1 blockade therapy for patients who are newly diagnosed
with glioblastoma.26 This work extends to other cancer types as well. In
Gillanders et al, patients with triple negative breast cancer (TNBC) are
being actively recruited to conduct a study on the e�cacy of adjuvant
therapies after administering neoantigen-based DNA vaccines. In this trial,
both groups will be given standard therapy as needed (ie. chemotherapy,
surgery, radiation therapy, etc.), however one group of patients will be given
the DNA vaccine alone. The other group will be given the vaccine along
with Durvalumab to test for increased immunogenicity. 27 The purpose of
these clinical trials, by both Johanns and Gillanders et al, is to investigate the
e�ects of using certain DNA vaccines in combination with standard
therapies. The �ndings from these trials will lead to future advancements in
the treatments used for diagnosed GBM patients.

The other type of nucleic acid vaccines, mRNA vaccines, currently holds
two widely acknowledged forms: non-amplifying mRNA and
self-amplifying mRNA, and each bears its mechanistic di�erences.23 The
main di�erence between the two is in the additional length of
self-amplifying mRNA, which is attributed to the nonstructural proteins
that extend the duration and amplitude of gene of interest (GOI)
expression.23 In contrast to DNA vaccines, mRNA vaccines do not have to
be transcribed by the host. Instead, the antigen-encoding genetic
information is directly delivered to antigen-presenting cells (APCs). After
reaching the host cell, the mRNA can be released and translated into
proteins which are then proteolyzed into peptide epitopes. Then, the
epitopes are sent to the Golgi apparatus, after which they are transported to
the plasma membrane and combined with MHC class I complexes via a
cross-presentation pathway.23 An immune response arises when CD8+ T
cells are activated as a result of the peptides reaching the cell surface of
APCS.

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Figure 6. Molecular mechanism of mRNA vaccines

Currently, there are studies being done assessing the potency of mRNA 
vaccines in patients with glioblastoma (GBM). In Sayour et al, the objective 
is to �rst assess the manufacturing feasibility and safety of a RNA-lipid 
particle (RNA-LP) vaccine and then evaluate the maximum tolerated dose 
in GBM patients.28 Participants will take part in a dose-escalation study 
using the Bayesian Optimal Interval (BOIN) design with an initial 
embedded accelerated titration design (ATD).28 In other studies, such as 
Desjardins et al, mRNA is currently being combined with dendritic cell 
vaccines and then evaluated for feasibility, potential adverse e�ects, and 
survival rates.29 Similar to clinical trials using DNA vaccines, the purpose of 
the experiments led by Sayour and Desjardins et al. is to advance the 
therapies available for GBM patients. As their approach uses less-studied 
mRNA vaccines, the current initiative is to evaluate the potency of these 
vaccines in patients.

4.4  Autologous Dendritic Cells (DC) Vaccines
  Autologous DC vaccines are composed of autologous, immature dendritic 
cells (DCs) with potential immunostimulating and antineoplastic abilities. 
Upon leukapheresis, immature dendritic cells are isolated and 
re-administered intratumorally. The immature DCs internalize and process

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the neoantigens or tumor-associated antigens (TAAs), migrate to the
lymphatic system, and expose the immune system to the TAAs, thereby
inducing a speci�c cytotoxic T-lymphocyte (CTL) response against the
cancer cells, leading to tumor cell lysis. The process of vaccination has the
potential to either reinforce the reaction against TAAs or induce a new
reaction. The mechanism of action for DC vaccines involves the MHC-II
molecules on the surface of the DCs, which make them professional
antigen-presenting cells (APCs). The DCs move between lymphoid and
nonlymphoid tissues to regulate chemokine gradients and cytokine
gradients and active T-killers. To create a DC vaccine, immature dendritic
cells are isolated from human blood, then utilize a cytokine cocktail and
autologous tumor antigens to promote maturation, then readminister the
autologous DCs back into the human body via the DC vaccine.30

Figure 7. An overview of the mechanism of action of autologous

DC vaccines

The e�cacy of the DC vaccine is dependent on the quantity of neoantigens
present in the tumor. The tumor mutational burden (TMB), representing
the frequency of neoantigen-associated mutations per megabase, is about 10
mutations/1.4 Mb.31 For patients undergoing TMZ chemotherapy, the
TMB typically experiences an increase, thus making neoantigen discovery
more feasible.

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The autologous neoantigen-based DC vaccine Neo-MoDC was tested in a
patient with advanced metastatic gastric cancer (35661819). The patient
had initially undergone laparoscopic-assisted D2 radical distal gastrectomy.
Multiplex immunohistochemistry (IHC) revealed low expression of PD-1
and high expression of PD-L1. Once the patient chose to alter their
treatment to receive the aforementioned trial’s treatment methods,
Neo-MoDC vaccines were created using autologous dendritic cells
generated from monocytes in peripheral blood mononuclear cells.14

Neo-MoDC was administered on its own initially, however after two
months, due to continued progression of the tumor, it was administered
alongside combination therapy with nivolumab—a monoclonal antibody
used to treat di�erent forms of cancer. The Neo-MoDC vaccine elicited a
healthy immunogenic response via an increase in neoantigen-speci�c CD4+
and CD8+ T cell activation, as well as an increase in neoantigen-speci�c T
cell clones in peripheral blood. Upon the onset of combination therapy, the
tumor volume experienced a rapid decrease, and continued application of
the Neo-MoDC vaccine resulted in complete regression for 25 months until
the present. To study T cell clone activation due to the Neo-MoDC
vaccine, primary tumor tissue and blood samples at di�erent intervals of
vaccination were collected. Activated peripheral blood lymphocytes (PBLs)
containing mutant peptides, TCRB clonotypes, and CDR3-regions of the
TCRB chain were also analyzed. Approximately 35.3% to 86.5% of TCRB
clones in PBLs were found in the tumor tissues, and the frequency of
tumor-enriched TCRB clones in PBLs increased from 0% to 16.8% after
four doses of Neo-MoDC.14 Evidently, Neo-MoDC induced
immunogenicity, however it required concurrent administration of
nivolumab to produce signi�cant results in tumor regression.

4.5  Immune Checkpoint Blockade Therapy

Many signaling pathways associated with the development of cancer. But
there are also key regulatory checkpoints termed immune checkpoints that
can negatively regulate these same signaling pathways. Immune checkpoint
blockade therapy takes advantage of these checkpoints and suppresses them,
thereby limiting tumor progression. Some known signaling molecules

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associated with pathways that lead to cancer development include PD-1,
PD-L1, and CTLA-4.32,33

Figure 8. Mechanisms of Immune Checkpoint Inhibitors (ICIs).
ICIs act on certain key proteins involved in the signaling pathways that

activate T cells. (A) T cells, via their CD28 protein, interact with
antigen-presenting cells (ACPs) and their CD80 or CD86 proteins. This

interaction can lead to subsequent activation of the T-cell. Another
signaling protein on the same T-cell, CTLA-4, has more a�nity for the

CD80 and CD86 proteins and can lead to subsequent inactivation of the
T-cell. Anti-CTLA-4 inhibitors prevent the inactivation of the respective
T-cell by disrupting the function of the CTLA-4 protein. (B) Cytotoxic

T cells CD8+ interact via their PD-1 protein with tumor cells via their

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PD-L1 protein. The interaction between these signaling proteins can lead
to negative regulation of the anti-tumor T cell response. Anti-PD-1 and

Anti-PD-L1 inhibitors prevent the binding of PD-1 and PD-L1 and thus
prevents inactivation of T cell anti-tumor responses.

Figure 9. A comparison of normal T-cell receptor binding vs. T-cell receptorbinding
after the addition of Anti-PD-L1 ligand and PD-1 blockade.(A) T-cell binds to PD-
L1 on tumor cells via PD-1 receptor; anti-tumor killing response is inhibited. (B) T-
cell’s PD-1 receptor binds toAnti PD-1 and PD-L1 binds to Anti-PD-L1; subsequent
activation of theanti-tumor killing response is observed.

More speci�cally, monoclonal antibodies are being used to target these
signaling molecules. When understanding the mechanisms by which
monoclonal antibodies function, we focus on a key immune cell, the B cell.
B cells are a very important part of the immune system since they have
antibodies on their surface membrane. Moreover, each B cell has antibodies
that are speci�c to one antigen and are useless against other antigens. This
can be advantageous or disadvantageous depending on the type of antibody
and respective antigen. When a B cell and its antibody interact with a

Berkeley Pharma Tech Journal of Medicine | 47



speci�c antigen, the B cell becomes activated and di�erentiates into either a
plasma cell or memory B cell. Plasma cells produce a vast amount of their
speci�c antibody and memory B cells remain in the host and serve as a part
of immune memory so that if they are needed again, they can be
activated.32,34 Looking further into antibodies or immunoglobulins, they are
made up of two heavy chains and two light chains and are arranged in a
Y-shape. The lower portion of the antibody contains an FC portion, which
remains the same amongst all antibodies and is then used to bind to cells of
the immune system. Cells of the immune system have an FC receptor that
binds to the FC portion of the antibody. The upper portion of the antibody
contains the variable region, which has many con�gurations and is designed
to attach only a single type of antigen. There are many ways by which
antibodies can stimulate the immune response which include by activating
the classical complement system, by attaching themselves to antigens in
order to neutralize toxins, by attaching themselves to certain receptors to
disrupt function of that receptor, by attaching themselves to a certain
pathogen or disease causing agent and agglutinate, or by acting as opsonins,
which involves antibodies attaching themselves to pathogens or disease
causing agents and making it convenient for the phagocytes to recognize and
destroy those pathogens that would have otherwise not been able to
recognize them because of primitive recognition structures associated with
certain immune cells.32,33,35 Another very important role they can play is
simulating antibody-dependent cell mediated cytotoxicity, in which
antibodies attach themselves to pathogens or abnormal cells and then they
help immune cells to recognize the pathogen and destroy it.32,35

Utilizing the information that antibodies provide an e�ective way of
targeting certain disease-causing agents and are very speci�c as to what
antigen they target, this can be translated over to mechanisms by which
monoclonal antibodies function. When treating a patient, it is possible to
translate this key process of recognition and subsequent action to stopping a
disease-causing pathway. Certain proteins or antigens that are associated
with harmful processes can be identi�ed and targeted by monoclonal
antibodies. Monoclonal antibodies are a single type of antibody [MP1] that
target a speci�c protein. There are many types of monoclonal antibodies on
the market today that have their own speci�c target protein.33,34 Many

Berkeley Pharma Tech Journal of Medicine | 48



monoclonal antibodies have been designed to target previously mentioned
key signaling molecules to inhibit immunosuppression and restore
antitumor responses of the immune system. These antibodies include
nivolumab, ipilimumab, avelumab, atezolizumab, retifanlimab, and many
more that have proven to be e�cacious against many cancer types, including
Glioblastoma.32 Multiple clinical studies have been undertaken to
understand the e�cacy of monoclonal antibodies against cancer.

Figure 10. An overview of the mechanism of action for a monoclonalantibody

Berkeley Pharma Tech Journal of Medicine | 49



Figure 11. Monoclonal Antibodies (MAb) against Tumor Cells. Monoclonal
antibodies can be found in many di�erent forms and thus based in many di�erent
ways. MAbs can be organized into three categories:
(1) Naked-MAb, (2) Immunoconjugates, (3) Multistep targeting. All these categories
represent recombinant or “chimeric” MAbs that are capable of mediating antibody
dependent cellular toxicity.

One such Phase I clinical trial, observed treatment with Neo-MoDC
(vaccine) and Nivolumab, which is a monoclonal antibody currently being
studied for glioblastoma therapy (FDA). PD-L1 and PD-L2 are ligands that
typically bind to PD-1 receptors in T-cells, which subsequently inhibit
T-cell proliferation and cytokine production (FDA).14 Nivolumab
competitively inhibits PD-1 by binding to the PD-1 receptor and preventing
PD-L1 and PD-L2 from binding, thus allowing enhanced T-cell function as
well as a resulting anti-tumor response. The recommended dosage for
nivolumab, as tested in unresectable and metastatic melanoma, metastatic
non-small cell lung cancer, advanced renal cell carcinoma, and classic
Hodgkin Lymphoma is typically 240 mg per 2 weeks or 480 mg 4 weeks, as
well as 3 mg/kg every 2 weeks for pediatric patients under 40kg. Some
possible adverse reactions include fatigue, rashes, musculoskeletal pain,
pruritus, diarrhea, nausea, asthenia, dyspnea, arthralgia, urinary tract
infection, and upper respiratory tract infection. Although its safety has not
been assessed in humans yet, there were no notable e�ects caused by

Berkeley Pharma Tech Journal of Medicine | 50



nivolumab in the male and female reproductive organs in monkeys, however
in animal models inhibition of PD-1 signaling led to an increase in the
severity of some diseases, such as tuberculosis in mice.14

Phase II Clinical Trial NCT03718767 was an interventional study of
neoadjuvant nivolumab in patients with glioblastoma. The patients were
due to receive 3mg of nivolumab every 2 weeks (anti-PD-L1 and PD-L2).
Its primary outcome measures were changes in the level of expression of
PD-L1 by tumor cells and lymphocytes, measured from the baseline until
the end of nivolumab treatment. The secondary outcome measures were
e�cacy, with the response rate assessed by Response Assessment in
Neuro-Oncology (RANO) criteria, and safety, with toxicity being assessed
by Common Toxicity Criteria (CTC). The study revealed that neoadjuvant
nivolumab resulted in enhanced expression of chemokine transcripts, higher
immune cell in�ltration and augmented TCR clonal diversity among
tumor-in�ltrating T lymphocytes, supporting a local immunomodulatory
e�ect of treatment.36 As such, the use of neoadjuvant nivolumab can be
used a method of early termination for developing tumor. Some key things
to mention are that this study involved the use of patients who have IDH1
or IDH2 mutated gliomas with hyper mutator phenotypes (HMP). These
patients had a high number of mutations in their tumors and the study
revolved around understanding if neoadjuvant nivolumab can stop or
reduce tumor size, showing characteristics of controlled tumor growth.
One of the drawbacks of this study was their secondary outcome measure of
improvements in quality of life, which was self-reported alongside symptom
severity and interference with daily activities. Self-reporting may lead to
biases or false speculation in the reports from the patients’ end, which in
turn would produce skewed secondary results.

An additional combined monoclonal antibody treatment for glioblastoma
(NCT03367715) that is currently being studied involves nivolumab and
ipilimumab (FDA). For the mechanism of action, ipilimumab binds to
CTLA-4 to block its interaction with the ligands CD80 and CD86—which
negatively regulate T-cells, therefore resulting in tumor penetrating
T-e�ector cell activation and proliferation (FDA). Inhibiting CTLA-4
signaling reduces T-regulatory cell function, contributing to an increase in

Berkeley Pharma Tech Journal of Medicine | 51

https://clinicaltrials.gov/ct2/show/NCT03718767
https://clinicaltrials.gov/ct2/show/NCT03367715?term=nivolumab%2C+ipilimumab&cond=Glioblastoma&draw=2&rank=1


T cell responsiveness. When ipilimumab and nivolumab are used
concurrently, PD-1 and CTLA-4 dual inhibition results in enhanced T-cell
function that is more e�ective than either antibody on its own, and they’ve
shown to produce more signi�cant antitumor responses.38

Currently, there are many trials being conducted to test the e�cacy of
single-monoclonal antibody treatments as well as combined monoclonal
antibody treatments. The aforementioned trials are just some of those few.

4.6  Adoptive Cell Therapies (ACT)

Adoptive Cell Therapies (ACT) involve the use of in vitro ampli�cation of
key immune cells, which include dendritic cells (DC), tumor-in�ltrating
lymphocytes (TIL) and cytokine-induced killer cells. These cells are
extracted from a patient, are ampli�ed, and then injected back into the
patient to enhance the tumor-killing response. More speci�cally TIL based
cell therapies have proven to be e�cacious in recognizing antigenic epitopes
on the surface of tumor cells and killing them.39,40,41 ACT with TILs has
been proven to be e�cacious against metastatic melanoma.42 Neoantigen
speci�c T cells were detected in the TILs of patients with metastatic
melanoma and neoantigens were identi�ed that increased the response of T
lymphocytes in the peripheral blood post-TIL infusion.33,43 However, the
process that goes into amplifying T cells is complex and it is di�cult to
obtain high a�nity TCR+ T cells and T cells produced in vitro do not last
for a prolonged period of time following infusion.33,40,42 In addition, the
tissue from which these T cells are extracted and then ampli�ed can lead to
variation amongst the types of antigens produced, making it less likely for a
shared/public treatment method.41,42

Berkeley Pharma Tech Journal of Medicine | 52



Figure 12. A sample work�ow of T-cell Therapy

In a Phase III clinical trial NCT05685004 a combination of TVI-Brain-1
immunotherapy and standard therapy compared to standard therapy alone
as a treatment for newly diagnosed MGMT unmethylated glioblastoma
patients. The general procedures include the collection and testing of cancer
tissue samples after surgery and chemoradiation therapy (radiation and
temozolomide). For the patients randomized into the investigational study
treatment group, they will also receive two vaccinations created from their
own cancer cells, undergo leukapheresis to collect immune T-cells from
their blood, and transfer of those activated e�ector T-cells after
chemoradiation therapy. All patients are followed with MRIs at follow-up
visits. This study acknowledged MGMT promoter methylation changes
and investigated whether these changes should be considered in the
treatment decision.44,45

There is a related therapy called the Chimeric Antigen Receptor (CAR) T
cell therapy which utilizes an antibody and T cell receptor complex. CAR
can be used to modulate host T cells in order to enhance the cancer killing
response of the immune system.41 CAR T-cell therapy is a type of
immunotherapy that uses a patient's own immune cells, called T-cells, to
�ght cancer. The therapy involves genetically modifying a patient's T-cells in
the laboratory to produce chimeric antigen receptors (CARs) on their

Berkeley Pharma Tech Journal of Medicine | 53

https://clinicaltrials.gov/ct2/show/NCT05685004?term=NCT05685004&draw=2&rank=1


surface.40,41,46 These receptors can then recognize and bind to speci�c
proteins on cancer cells, which helps the T-cells to identify and attack the
cancer cells.

However, the use of CAR T-cell therapy for the treatment of solid tumors is
still being studied in the early stages of clinical testing. One of the challenges
in treating solid tumors with CAR T-cell therapy is that the CAR T-cells
need to be able to penetrate the tumor microenvironment and e�ectively
target the cancer cells, which can be di�cult to achieve.41,46

Figure 13. A simple work�ow of CAR-T cell therapy

In a Phase I Clinical trial NCT04003649, the e�cacy of IL13R alpha
2-CAR T cells when given alone or together with nivolumab and
ipilimumab and their e�ects on treating patients with glioblastoma that has
come back (recurrent) or does not respond to treatment (refractory).
Biological therapies, such as IL13R alpha 2-CAR T cells, use substances
made from living organisms that may attack speci�c glioma cells and stop
them from growing or kill them. Immunotherapy with monoclonal
antibodies, such as nivolumab and ipilimumab, may help the body's
immune system attack the cancer, and may interfere with the ability of
tumor cells to grow and spread.47 It was found that IL13R alpha 2-CAR T

Berkeley Pharma Tech Journal of Medicine | 54

https://clinicaltrials.gov/ct2/show/record/NCT04003649?term=car+t&recrs=ad&cond=glioblastoma&draw=4&rank=5


cells enhance anti-tumor activity and T-cell persistence and showed evidence
of bioactivity in patients. In addition, it was found that local intracranial
delivery of CAR T cells increased anti-tumor e�cacy as compared to
intravenous administration.40,47 Overall, this study de�ned parameters for
the clinical translation of CAR T cell therapy for the treatment of brain
tumors.

4.7  Combination Therapies with Neoantigen-based Vaccines

The use of tumor vaccines, monoclonal antibodies, and adoptive cell
therapies are potential and e�cacious treatment methods for Glioblastoma.
Speci�cally looking at tumor vaccines, they have extreme potential when
developing personalized treatment methods for patients. Anti-tumor
vaccines, such as the proposed neoantigen vaccines, activate certain
pathways in the host immune system that can create a susceptible
environment for concurrent or subsequent treatment methods.48,49 This is
an important aspect to note when considering neoantigen-based vaccines as
a treatment method for Glioblastoma. As shown in previous clinical trials
and studies, cancer vaccines are a very innovative way to approach cancer
treatment but they have very low e�cacy, with an objective clinical response
rate of only >7% and an overall rate of clinical bene�t of only ~20%.49,50

There is no question that cancer vaccines stimulate and modulate the
immune system, and this can be taken advantage of when treating patients.
Utilizing neoantigen-based vaccines can prime the host immune system to
be more responsive to subsequent therapies that can enhance the
tumor-killing response of the host immune system.48

In a Phase II clinical trial NCT03047928, the programmed death 1 (PD-1)
regulatory antibody Nivolumab and a peptide vaccine consisting of
programmed death ligand 1 (PD-L1) and Indoleamine 2,3-dioxygenase
(IDO) peptides were tested in patients with metastatic melanoma.51 The
primary endpoints for this study was feasibility and safety of the combined
treatment. The secondary endpoints were e�cacy and immunogenicity.
Overall, the study revealed that the vaccine-reactive T cells comprised CD4+
and CD8+ T cells with activity against IDO- and PD-L1-expressing cancer
and immune cells, thus increasing the immunomodulatory e�ect of the
combination therapy.51,52

Berkeley Pharma Tech Journal of Medicine | 55

https://clinicaltrials.gov/ct2/show/NCT03047928


There are many other clinical trials currently being conducted to
understand the use of combination therapies as a treatment method for
di�erent types of cancers including Glioblastoma. Overall, while further
research is needed to fully understand the potential of neoantigen vaccine
combination therapies in glioblastoma, early results suggest that these
approaches may hold promise as a way to improve outcomes for patients
with GBM.

5. Practical Considerations

Glioblastoma is a type of brain cancer that is di�cult to treat. Novel
neoantigen-based treatment methods are being explored as a potential
solution to this problem. Neoantigens are unique proteins that are
expressed on the surface of cancer cells, but not on healthy cells, making
them a promising target for cancer treatment.53 Here are some practical
considerations when exploring novel neoantigen-based treatment methods
for glioblastoma:

Identi�cation of neoantigens: The �rst step is to identify the
neoantigens that are present in the glioblastoma cells. This can be
done through genomic analysis, transcriptomic analysis, and/or
proteomic analysis. The identi�cation of neoantigens is critical for
developing a personalized treatment plan.

Personalized treatment plans: Because each patient's glioblastoma is
unique, a personalized treatment plan is necessary. This involves
identifying the patient's speci�c neoantigens and developing a
treatment plan that targets those speci�c neoantigens.

Delivery methods: One of the challenges of neoantigen-based
treatment methods is delivering the treatment to the brain.
Traditional delivery methods, such as intravenous injections, are not
e�ective for brain tumors. Therefore, new delivery methods, such as
direct injection into the brain, are being explored.

Immunogenicity: It is important to ensure that the
neoantigen-based treatment method is immunogenic, meaning that

Berkeley Pharma Tech Journal of Medicine | 56



it stimulates an immune response. This is critical for the treatment
to be e�ective.

Combination therapies: Neoantigen-based treatment methods may
be more e�ective when used in combination with other therapies,
such as chemotherapy or radiation therapy. Therefore, the potential
for combination therapies should be considered.

Clinical trials: Clinical trials are necessary to test the safety and
e�cacy of neoantigen-based treatment methods. These trials should
be designed to address the speci�c challenges associated with
treating glioblastoma, such as delivery to the brain and the
development of personalized treatment plans.

Overall, exploring novel neoantigen-based treatment methods for
glioblastoma requires careful consideration of several practical factors,
including identi�cation of neoantigens, personalized treatment plans,
delivery methods, immunogenicity, combination therapies, and clinical
trials.

6. Conclusion

Glioblastoma remains a formidable challenge in the �eld of oncology due to
its aggressive nature and limited treatment options. However, advancements
in immunotherapeutic approaches, such as neoantigen-based vaccines,
immune checkpoint blockers, and adoptive cellular therapies, have
demonstrated promising e�cacy in repressing glioblastoma tumor cells.
Our comprehensive review of scienti�c literature and clinical trials has shed
light on the potential of these treatment methods and identi�ed areas for
improvement to further enhance their e�ectiveness.

Neoantigen-based vaccines have shown promise in priming the immune
system to recognize and attack cancer cells displaying unique neoantigens.
Protein-peptide vaccines have been utilized to stimulate a speci�c cytotoxic
T-lymphocyte (CTL) response against tumor cells expressing targeted
neoantigens. The clinical trials conducted by Hilf et al. and Keskin et al.
demonstrated increased overall survival and progression-free survival in

Berkeley Pharma Tech Journal of Medicine | 57



patients who received neoantigen-based vaccines, albeit with some side
e�ects. Ongoing trials, such as the Reardon et al. trial, are investigating the
combination of neoantigen-based vaccines with other therapies to assess
their synergistic e�ects.

Nucleic acid vaccines, including DNA and mRNA vaccines, have also
emerged as potential treatment methods. DNA vaccines introduce a gene
encoding antigens using bacterial plasmids as vectors, while mRNA vaccines
deliver the antigen-encoding genetic information directly to
antigen-presenting cells. Clinical trials led by Johanns et al. and Sayour et al.
are evaluating the safety, feasibility, and immunogenicity of personalized
neoantigen-based DNA and mRNA vaccines in glioblastoma patients,
respectively. Combination therapies with DNA vaccines, such as the trial by
Johanns et al., show promise in enhancing immunogenicity and improving
patient outcomes.

Autologous dendritic cell (DC) vaccines aim to stimulate a speci�c CTL
response against cancer cells by presenting neoantigens or tumor-associated
antigens to the immune system. The Neo-MoDC vaccine demonstrated
immunogenicity and induced tumor regression in a patient with advanced
metastatic gastric cancer when administered alongside nivolumab. The
�ndings suggest the potential of autologous DC vaccines in treating
glioblastoma, but further research is needed to optimize their e�cacy and
explore combination strategies.

In addition to vaccine methods, immune checkpoint blockade therapy,
particularly through the use of monoclonal antibodies, has shown
promising results in the treatment of glioblastoma and other cancers. By
targeting key signaling molecules such as PD-1, PD-L1, and CTLA-4,
immune checkpoint inhibitors can suppress immunosuppression and
restore anti-tumor responses, leading to improved outcomes for patients.
Monoclonal antibodies provide a highly speci�c and e�ective way to target
disease-causing proteins or antigens. By utilizing their ability to recognize
and bind to speci�c targets, monoclonal antibodies can disrupt harmful
pathways and stimulate the immune response against cancer cells. Various
monoclonal antibodies, including nivolumab, ipilimumab, avelumab, and

Berkeley Pharma Tech Journal of Medicine | 58



atezolizumab, have shown e�cacy in glioblastoma and other cancer types.
Combination therapies, such as the concurrent use of nivolumab and
ipilimumab, have demonstrated enhanced T-cell function and signi�cant
antitumor responses. These combinations target multiple checkpoints
simultaneously, leading to more e�ective immune responses against cancer
cells.

Adoptive cell therapies, such as TIL-based cell therapies and CAR T-cell
therapy, o�er another avenue for glioblastoma treatment. TIL-based cell
therapies can recognize and kill tumor cells, while CAR T-cell therapy
genetically modi�es a patient's T-cells to enhance their ability to target and
attack cancer cells. However, further research is needed to optimize these
therapies for solid tumors like glioblastoma.

To further advance glioblastoma treatment, several areas of improvement
should be considered. First, optimization of sequencing methods, such as
whole-genome sequencing (WGS), whole-exome sequencing (WES), and
next-generation sequencing (NGS), can enhance the identi�cation of
neoantigens and somatic mutations e�ciently in terms of time and cost.
Additionally, strategies to overcome immune evasion mechanisms employed
by glioblastoma, such as upregulation of immune checkpoint molecules,
should be explored. Combination therapies involving neoantigen-based
vaccines, immune checkpoint blockers, and adoptive cellular therapies hold
promise in overcoming resistance and enhancing treatment responses.

In conclusion, the development and utilization of neoantigen-based
vaccines, immune checkpoint blockers, and adoptive cellular therapies have
opened new avenues for glioblastoma treatment. While these treatment
methods have demonstrated e�cacy, ongoing research and improvements in
sequencing techniques, combination therapies, and immunomodulatory
strategies are crucial for achieving further breakthroughs. The integration of
personalized medicine approaches and a deeper understanding of the
complex interplay between the tumor microenvironment and the immune
system will contribute to the development of more e�ective and targeted
therapies for glioblastoma patients, ultimately improving their prognosis
and quality of life.

Berkeley Pharma Tech Journal of Medicine | 59



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