The Application and Prospect of Immune Checkpoints based on PD1

and CTLA4

Ruining Oscar Hang

1,a

, Jinyu Zhou

2,*

, Rui Yuan

3,b

, Huafeng Zheng

4,c

, Xinyuan Li

5,d

and Yuze Guo

6,e

The Hun School of Princeton, Princeton, U.S.A.

West China School Of Public Health, Sichuan University, Chengdu, 610227, China

School of Minerals Processing and Bioengineering, Central South University, Changsha, China

Dulwich International High School, Zhuhai, China

Victoria Hill School (Partnered with Rosedale Academy), Kunming, China

International Center, Jinan Foreign Language School, Jinan, China

david.zheng22@stu.dulwich.org,

phoebem_lxy@outlook.com,

ReginaldGuo@163.com

Keywords: Malignant Tumors, Immunotherapy, Immune Checkpoint Inhibitors, PD-1, CTLA-4ACM Reference Format.

Abstract: Malignant tumors are currently one of the greatest health challenges the world is facing, ranking first among

the various lethal factors that cause death each year. There is a high probability of relapse after treatments

once treated with traditional approaches. Immunotherapy typifies a promising treatment method to increase

survival rates among patients at advanced stages. So far, however, patients can only receive limited benefits

from this novel therapy. In this article, we explore two important immune checkpoints, PD-1 and CTLA-4,

and discuss different factors influencing the functions of the immune checkpoint inhibitors. We also review

the recent developments in the field from the point of view of combinatory therapies. Research proposals

aimed to improve immunotherapies are also included to open new perspectives in enhancing the efficacy and

safety of the treatment of malignant tumors.

1 INTRODUCTION

Chemotherapy, radiation, and surgery are considered

the cornerstones of conventional cancer treatment.

However, it remains difficult for conventional

treatment programs to completely remove tumor cells

largely due to tumors’ ability to grow rapidly, and the

tendency of developing metastasis, and resistance to

radiotherapy and chemotherapy (Hanahan, Weinberg

2011). They also impose lethal effects on normal

cells, greatly harming the patients’ overall health.

Therefore, highly specific treatments with long-

lasting effects have become the primary target in

treating malignant tumors.

The success of immunotherapy is based on both

cancer destruction through the initiation of the host

immune system and the regulation of the cancer-

immune environment (Robert 2020). Scientists have

confirmed that immune checkpoints such as CTLA-4

and PD-1/PD-L1 signaling pathways play an

important role in regulating T cell immune response.

The immune checkpoints blockade can effectively

destroy tumor cells without compromising CTL

function, strengthen the outcome of anti-tumor

immunity. The finding of immune checkpoints

opened up a new path in treating malignant tumors

and greatly promote the development of checkpoint

inhibitor drugs (Freeman 2000). Since 2011, the FDA

has successively approved multiple PD-1/PD-L1

inhibitors for the treatment of various tumors such as

metastatic or unresectable melanoma. Immune

checkpoint inhibitor therapy provides novel and

effectual treatment methods for tumor treatment. It is

believed that more breakthroughs can be obtained in

the near future.

However, the research related to checkpoint

inhibitors is in the early stage, and we have not yet

fully understood its biological characteristics and

related signal pathways. In addition, checkpoint

inhibitors have some potentially serious side effects,

many of which are due to an overactive immune

response, which is related to inflammation of the

intestines, lungs, heart, skin, and other organs.

Approximately half of the advanced patients have no

obvious response to checkpoint inhibitors or no

response at all. Some people live longer without

Oscar Hang, R., Zhou, J., Yuan, R., Zheng, H., Li, X. and Guo, Y.

The Application and Prospect of Immune Checkpoints based on PD1 and CTLA4.

DOI: 10.5220/0011312900003443

In Proceedings of the 4th International Conference on Biomedical Engineering and Bioinformatics (ICBEB 2022), pages 901-909

ISBN: 978-989-758-595-1

901

treatment or live longer before their condition

worsens.

The immune check point-therapy and

combination strategies can provide advanced cancer

patients with superior treatment which can control or

even cure the disease. The specificity, adaptability,

and great capacity allow multiple biomarkers to work

inside the body. Despite the overall survival for

patients have improved, there are limitations and

challenges inherent in immune checkpoints therapy.

Emerging data and observation suggest that we need

to better understand the reason why there are certain

cancer types that refuse to respond and find the sealed

answer. Motivated by these developments, we now

revisit the critical mechanisms and recent findings

that associated with immune checkpoint therapy,

consider the limitation as well as challenges appear

during the clinical application, and expand upon the

functional roles to find possible approaches to tackle

the corresponding problems of immunotherapy.

2 APPLICATIONS AND

IMPROVEMENTS

2.1 Combination Therapy of Novel

Oncolytic Adenovirus with PD-L1

Inhibitors Resulted in Strengthened

Anti-cancer Effect

Malignant melanoma (MM) is a type of malignant

tumor derived from melanocytes. Early-stage

malignant melanoma is often treated by surgical

resection and a longer survival can be obtained.

However, in the middle and late stages, surgical

resection alone is not good for patients with

melanoma. Chemotherapy, radiotherapy, and

targeted therapy are the main therapies for melanoma,

but the efficacy is still not optimistic due to relapse

and drug resistance.

The emergence of PD-L1 antibodies has

completely altered the treatment strategy for

advanced and metastatic melanoma. However, it has

been reported 40%–60% of melanoma patients do not

gain any notable recovery, and a great portion of

recipients relapses within two years of the treatment.

The low efficiency of the immune checkpoint

inhibitors is largely due to their low response rate and

potent immunosuppressive effect that creates a "cold"

immune tumor microenvironment (TME) (Imbert et

al. 2020). Recent researches have shown that through

infecting the tumor lesion with engineered Oncolytic

adenoviruses, the resulting inflammatory response

can trigger the release of a series of immunoglobulins

and signaling molecules including proinflammatory

cytokines and an influx of NK cells, T cells, and

antigen-presenting cells (APC), consequently

generating the desired “hot” tumor microenvironment

(LaRocca, Warner 2018). Garofalo and Bertinato

treat mice models with melanoma tumors using the

anti-PD-1 antibody combined with a newly designed

oncolytic adenovirus containing modified AdV-D24-

inducible costimulator ligand AdV-D24-ICOSL-

CD40L that only targets and replicates in cancer cells

by intratumor injection (Garofalo et al. 2021),

resulting in a strengthened anti-cancer ability and

immunogenic cell death in vitro and a significant

decrease in tumor volume while ensuring a 100%

survival rate in vivo. The findings demonstrate that

oncolytic adenovirus-expressing potent immune

modulators can drive the systemic efficacy of PD-1

blockade, enhancing anti-cancer effectiveness and

survival (see Figure 1).

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Fig 1. (Garofalo et al. 2021) (A) Tumor volume (mm3) measured through the study. The treatment was performed once per

day on days 1–6. The mice were treated according to the scheme (Table 1) with viruses (i.t.) and anti PD-1 antibody (i.v.) (B)

At the end of the study, mice were sacrificed and tumors harvested for weight assessment. (C, D) Tumor volume measurement

on days 6 and 20, respectively. (E) Body weight measurements throughout the study. (F) Survival profile was calculated by

Kaplan–Meier test. (H) Evaluation of CRT exposure after the treatment with oncolytic adenoviruses AdV-24-ICOSL-CD40L

and AdV-D24, and in combination with anti PD-1. CRT exposure was measured in the end of the study (after mice sacrifice)

with anti-calreticulin antibody staining and subsequent flow cytometry analysis (Beckman-Coulter Cytomics FC500). (G)

Assessment of ATP release after the treatment

However, there still contains two major concerns,

the potential risk of causing strong immune side-

effects and the lack of efficacy on tumors that are

undergoing metastasis.

Nanoparticle as a kind of delivery vector is one of

the good strategies to solve these issues (Kosmides

2017). Rather than the intratumor injection, a

nanoparticle delivery system that combines blockade

of PD-1 with the engineer oncolytic adenovirus AdV-

D24-ICOSL-CD40L can be hypothesized in order to

investigate the efficacy on tumor cells in vivo.

Optimistically, this nanoparticle delivery system may

increase the targeting and efficacy of oncolytic

viruses and anti-PD-1 antibodies, while reducing the

immune response of nontarget organs.

2.2 Restricting Glycolysis Preserves T

Cell Effector Functions and

Augments Checkpoint Therapy

(Renner et al. 2019)

The glycolytic activity of tumor cells is enhanced,

and lactic acid is accumulated and acidified in the

tumor. T and NK cells absorb lactic acid and impair

effector functions. But diclofenac can reduce the

secretion of lactic acid by inhibiting the lactate

transporters MCT1 and MCT4 and enhance T cell

function (figure2). So, inhibition of glycolysis

improves treatment at checkpoints. In addition, the

reduction of lactic acid by diclofenac has nothing to

do with changes in glycolysis-related proteins and

MCT expression profiles. And MCT inhibition does

not impair the in vitro function of T cells.

Figure 2: Explains a negative correlation between

glycolytic activity in tumors and response to check point

therapy.

However, the study mentioned above only has an

experimental group and does research on several

kinds of objects at the same time. Then a new clinical

trial is designed. The purpose is to study whether

reducing lactic acid secretion can improve T cell-

mediated killing of melanoma cells. Patients over 18

years of age, with good nutritional status, and tumor

stages in stage I and stage II will be included. And

patients with other tumors, such as pancreatic cancer,

gastric cancer, and patients undergoing anti-PD-1

therapy will be excluded.

The Application and Prospect of Immune Checkpoints based on PD1 and CTLA4

903

100 melanoma patients from five medical centers

will be divided into a control group and an

experimental group. The experimental group will be

treated with diclofenac, while the control group will

be treated with an equal dose of normal saline. The

researchers will follow up 100 patients for six months

and test the anti-tumor immunity of cells in two

groups. Compared with control cells, more lactic acid

and stronger anti-tumor immunity are expected to be

detected in the experimental group. Because reducing

lactic acid secretion by diclofenac may enhance the T

cell-mediated killing effect in melanoma cells.

Continue to add lactic acid to the experimental group

to a high concentration, which will reverse the

positive effect of diclofenac, resulting in suppression

of anti-tumor immunity as T cells may die when the

concentration of lactic acid increases. Overall,

reducing the tumor efflux of lactate can enhance the

immune response to checkpoint suppression.

2.3 Caffeine-Enhanced Anti-tumor

Activity of Anti PD-1 Monoclonal

Antibody

In this study, the authors evaluated the anti-tumor

activity of caffeine and anti-PD1 mAb combination

therapy against B16F10 melanoma tumors (Tej,

Neogi, Nayak 2019). They found that combination

therapy showed a decrease in the infiltration of

CD4+CD25+ T regulatory cells, an increase in

infiltration of CD4 T lymphocytes, CD8 T

lymphocytes, intra-tumoral TNF-α, and IFN-γ levels.

Experiments have confirmed that the combination of

anti-PD1 mAb and caffeine for tumor treatment

produced good results due to the blocking of the a2a

receptor and PD1.

The immunosuppressive environment in the

tumor microenvironment (TME) has always been an

obstacle to immune checkpoint inhibitors, of which

the CD39-CD73 adenosine pathway is an important

participant in the immunosuppressive environment.

The immunostimulating molecule ATP is converted

to AMP through CD39, AMP is converted to

immunosuppressive adenosine through CD73. Once

adenosine combines with its receptors, it will

promote tumor immune escape. To sum up, there are

two primary aspects of immunosuppressive

adenosine: one is targeting CD73 and/or CD39 to

inhibit the production of adenosine, and the other is

targeting the A2a receptors to block adenosine

signaling (Leone, Emens 2018). Antibodies that

target CD73 or CD39 block adenosine production and

relieve immunosuppression, and they can also be

used as both a single drug treatment and a synergistic

anti-tumor effect in combination with immune

checkpoint inhibitors. Referring to the previous

article (Tej, Neogi, Nayak 2019), some experiments

were designed in this paper to study the effects on

tumors by comparing caffeine as an antagonist of

A2aR and TTX-030 (BMS-986179) as an anti-CD39

antibody (anti-CD73 antibody) combine with anti-

PD1 monoclonal antibodies, respectively. The

following design experiments help to further explore

the effectiveness of combination therapies.

(The design ideas of this experiment refer to the

previous article (Tej, Neogi, Nayak 2019).)

Mice were randomly divided into

(A) Anti-PD1 mAb + caffeine group: receive a

combination of injection of anti-PD1 mAb and

caffeine in drinking water

(B) Anti-PD1 mAb + TTX-030（BMS-986179）

group: receive an injection of anti-PD1 mAb and

TTX-030（BMS-986179）

After 6 weeks of treatment, calculate tumor

growth rates of individual mice from each group

through dividing tumor size. The efficacy of different

combination therapies is then evaluated in the

following areas as shown in Figure 3.

Figure 3: Evaluation of combination therapy in different aspects.

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904

2.4 MHC Protein Confer Differential

Sensitivity to CTLA-4 and PD-1

Blockade in Untreated Metastatic

Melanoma

Although immune checkpoint blockades (ICB) are

treatments for cancer, the mechanism to cure the

immune system but not directly treating cancer and

the antitumor immune response is highly dependent

on the T-cell cognition of surface-expressed antigen

which is the major histocompatibility complex

(MHC), therefore the reduction of, or the loss

proteins associated with MHC protein can potentially

be a mechanism which tumor escape antitumor

response and induce resistance to the antibodies

during ICB course.

When they examined the overall survival, low

average tumor MHC class I expression (smaller and

equal to 50%) (S. J. Rodig D.G 2018) was

characterized with lower overall survival for the

patients that started with blockade IPI; better overall

survival for the patients that started with NIVO

attributed to unaffected tumor MHC class II

expression. The authors concluded the anti-CTLA-4

response primarily relied on the melanoma surface

MHC class I expression. In comparison, the primary

response to anti-PD-1 is associated with existing

interferon-gamma-mediated

Figure 4: Shows the difference in survival for two group which started with different check-point inhibitors, along with the

MHC class I surface expression.

There are limitations inherent in this

investigation, the association and responses to single

blockade IPI and NIVO lack of experimental results

to confirm the observation, etc.

According to the main findings of the articles, the

downregulation of the major histocompatibility

complex (MHC) is a mechanism of evading

antitumor immune response after the ICB, critically,

the primary resistance to CTLA-4 blockade was

attributed to the reduced melanomaMHC class I

expression. Down-regulation of MHC protein surface

expression is common in melanoma (seliger 2000)

before any approaches have been applied. Whereas

the primary response to anti-PD-1 blockade is

associated with pre-existing interferon-gamma

mediated immune activation.

There are hypotheses stated that interferon-

gamma is a profound molecule in manipulating the

MHC class I surface expression (Delgado, Ganea

2000, B. Seliger S.H et al 1997). the down-regulation

of MHC class I expression is due to the lack of

essential components in the expression pathway.

interferon-gamma is a significant factor there in terms

of modulating the transduction pathway and induce

the production of the new proteasome to replace the

old one or renovate it (B. Seliger S.H et al 1997).

2.5 Compensatory Upregulation of

PD-1, LAG-3, And CTLA-4 Limits

the Efficacy of Single-agent

Checkpoint Blockade in Metastatic

Ovarian Cancer

It is not clear whether the multiple receptors work

together in the process of specific immunity can serve

a better result for combining the ligands on the cancer

cell to the surface of T cells. Therefore, the co-inhabit

method is worth researching.

The Application and Prospect of Immune Checkpoints based on PD1 and CTLA4

905

Figure 5: Shows the different survival rate of mice with different receptors.

According to figure 4, researchers have selected

three receptors, PD-1, LAG-3, and CTLA-4, which

are the immune checkpoints of T cells to regulate the

replication of metastatic ovarian cancer cells (Huang

et al 2016). The researchers test the survival rate of

mice with PD-1, PD-1 and LAG-3, PD-1 and CTLA-

4 blocking group, and triple blocking group. The

experiment result shows that the mice(C57BL/6) that

have two or three inhabitation pathways are slightly

more effective in dealing with the repelling of cancer

cells. The PD-1KO mice have little cytotoxic

materials when they have three inhabit pathways

compare to the normal mice.

Researchers established an ovarian tumor model

for collecting the data. Also, they splited TALs

(Tumor-associated lymphocytes) and TILs (Tumor-

infiltrating lymphocytes) from lymphocytes to

analyze. By reviewing the result, they knew that

several receptors are responsible for inhibiting

metastatic ovarian cancer, and the blocking of a

single receptor causes the upregulation of the co-

inhibitory system. The mice combining four

antigens can secret more cytotoxic materials to attack

normal cells than the mice with triple checkpoint

pathways. The mice with LAG-3, CTLA-4, and PD-

1 blockage or the dual inhibition pathways mice are

more effective to block the replication of metastatic

ovarian cancer than single pathway since knocking

out of PD-1 or LAG-3 can enhance the ability of the

other receptors to combine with the antigen.

Huang et al. provide evidence suggesting that the

block of LAG-3 and CTLA-4 can increase the

survival rate of PD-1KO mice. Similarly, the block of

PD-1 and CTLA-4 can enhance the survival rate of

LAG-3KO mice significantly (Huang et al 2016). A

single checkpoint pathway is not efficient compare to

dual checkpoint pathways. However, more than three

receptors' mice do not serve an excellent response to

the wild-type mice. Researchers should test the

relation between survival rate and cytotoxic materials

for finding the regulation. Researchers can analyze

300 mice in the research and divide them into three

groups. The first group of mice (PD-1KO) have

LAG-3, CTLA-4, and IgG; the second group will

contain the same receptors while they have no

treatment; the third group (PD-1KO) will be knocked

out the other receptors and only left CTLA-4. After

separate the groups, the researchers follow up these

ICBEB 2022 - The International Conference on Biomedical Engineering and Bioinformatics

906

mice for 6 months to compare the overall survival

with three different groups, which can find out

whether more than three receptors can enhance the

secret of cytotoxic materials.

2.6 Immune Microenvironment

Modulation Unmasks Therapeutic

Benefit of Radiotherapy and

Checkpoint Inhibition

Although the clinical effect of ICIs in the treatment

of solid tumors is exciting, many patients haven’t

achieved a sustained response. One of the main

barriers to treatment is the immunosuppressive tumor

immune microenvironment (TIME). Therefore,

researchers made a hypothesis of which the

combination of targeted radiotherapy and time-

dependent immunomodulation was able to improve

the ICI response rate of solid tumors. To test their

hypothesis, head and neck tumor was used on

C57BL/6J male mice that are 8-10 weeks of age to

explore the tumor characteristics limiting the efficacy

of immune checkpoint inhibitors in solid tumors and

to develop combination therapy strategies to

maximize their advantages. After the tumor became

established, mice received combinatory treatments

involving immune checkpoint inhibitions, tumor-

directed radiation, and immunomodulation of

cyclophosphamide (CTX) and L-n6-(1-iminoethyl)-

lysine (L-NIL). The result is that they found that

modulation of TIME using CTX and L-NIL,

combined with two checkpoint inhibitors and

radiotherapy, had better effects than these treatments

alone. It resulted in more than 70% of established

mEER tumor rejection, doubling the median survival

rate of the B16 melanoma model (Newton J.M et al.

2019).

Figure 6: (Newton J.M et al. 2019) The average tumor area and percent survival of mice before the first euthanasia under

different treatment combinations (CTX/L-NIL immunomodulation combined with α PD-1/ α CTLA-4 and tumor directed

radiation are collectively called the “CPR” regimen).

The previous study (Newton J.M et al. 2019) has

shown that regulating the immune microenvironment

can release the efficacies of ICIs and radiotherapy to

activate immune rejection in the therapy of refractory

tumors. However, it only made experiments on head

and neck cancer. Therefore, the purpose of the new

experiment is to see if the same regimen works on

lung cancer and gastric cancer, since these two

cancers are solid tumor which will respond to ICIs

used well, and they are very common. This study will

also use C57BL/6 male mice aged 8-10 weeks. After

tumors become established, treatments will start.

There will have two sets of experiments, one for lung

cancer, and one for gastric cancer. Each set of the

experiments will have two groups. One group with

modulation of TIME uses combination therapy of

PD-1 and CTLA-4 inhibitors, radiotherapy, and

immunomodulatory drugs: CTX and L-NIL. Another

group is the control experiment without modulation

of TIME, combining dual inhibition and

radiotherapy. All experiments will be replicated for at

least twice, and each experiment will have 5-10

samples in average. For the result, the hypothesis is

that the strategy of combining tumor-targeted

radiation with tumor immune microenvironment

regulation can improve the ICI response rate of lung

and gastric tumors.

3 CONCLUSION

This paper first explores the monoclonal antibody

immunotherapy of PD-1 in tumors. The novel

combination therapy of Oncolytic Adenovirus with

Anti-PD1 inhibitors presents an alternative treatment

therapy in treating Malignant melanoma. In addition,

the inhibition of glycolysis preserved T cell and NK

cell function, and enhanced anti-PD-1 treatment

The Application and Prospect of Immune Checkpoints based on PD1 and CTLA4

907

response is observed. Checkpoint immunity also

plays an important antitumor role in combination

therapy. The combined blockade of the a2a pathway

and pd1 pathway showed more effective anti-tumor

activity than monotherapy. Another study concluded

the primary response to anti-CTLA-4 is rely on the

melanoma surface MHC class II expression and that

anti-PD-1 is associated with existing interferon-

gamma-mediated immune activation. Besides,

knocking out of PD-1 and keeping the other co-

inhibitory workers can enhance the repelling of

metastatic ovarian cancer cells. Finally, a therapy of

combining modulation of tumor immune

microenvironment with dual checkpoint inhibition

(PD-1 and CTLA-4), and radiotherapy has shown a

good effect.

This research is of great significance because the

immune checkpoint is widely studied in medicine. It

is widely used in the treatment of cancer, such as

hepatocellular carcinoma (HCC), urinary system

malignant tumors, breast cancer, recurrent/metastatic

nasopharyngeal cancer and lung cancer. In addition,

the Immune checkpoint plays an important role in

acute pancreatitis (AP). Besides, scientists have done

a lot of research on the interaction between intestinal

flora and immune checkpoint inhibitors.

Although ICIs have played an important role in

cancer treatment and shown great promise in so many

different diseases, much more research on long-term

toxicity and survivorship issues is needed since new

side effects were found (Kottschade 2019). They

were often referred to as immune-related adverse

events (irAEs) or immune-mediated adverse

reactions. Moreover, as these strategies are used in

more and more malignant tumors, more side effects

are constantly observed, including but not limited to

endocrine toxicity, rheumatologic toxicity. These

side effects may be life-threatening, so in the future,

researchers should pay attention to acute toxicity,

long-term toxicity, and other treatments to improve

the life of patients after cure.

Recently, there is a pronounced increase in the

number of articles listed in PubMed that associated

with bispecific antibodies (biAbs) in the

immunotherapy of cancer, apparently, this innovation

has become a crucial part of immunotherapy for the

next generation. However, in cancer immunotherapy,

the competition never stops, another candidate

includes chimeric antigen receptor T cells, NK cell-

engaging biAbs, or macrophage-engaging biAbs.

More importantly, they all have the capacity to prove

they can potentially control, or even cure the

malignant tumor.

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