Immune Checkpoint Inhibitor Therapy: Application in

Non-Small Cell Lung Cancer

Yumeng Liu

Chengdu University of Technology, Chengdu, China

Keywords:

Immune Checkpoint Inhibitor, Non-Small Cell Lung Cancer, Therapy.

Abstract: Lung cancer is the most deadly disease in the world. The common treatment options include surgery,

chemotherapy and radiotherapy, and targeted therapy can also be used selectively for those with positive

driver genes. However, the 5-year survival rate of lung cancer patients is still low. Non-small cell lung cancer

(NSCLC) is the most common type of lung cancer, and there is an urgent need for new treatment methods in

clinic. Immune checkpoint inhibitors have changed the treatment landscape for advanced NSCLC, showing

advantages in first-line, second-line and even multi-line therapy for patients with NSCLC. In recent years,

immunotherapy has provided a possibility for patients with NSCLC as a new and effective tumor treatment

method. This review reviewed the mechanism of action, clinical application, immune escape mechanism and

adverse reactions of immune checkpoint inhibitor therapy in non-small cell lung cancer.

1 INTRODUCTION

Lung cancer has become a global problem

endangering human health, causing more than 1.6

million deaths every year. In recent years, targeted

therapy has been proposed for patients with genetic

dysfunction of NSCLC, but many patients do not have

oncogenic factors such as epidermal growth factor and

anaplastic lymphoma kinase, and drug resistance is

inevitable (Low, et al., 2019). It has become a trend to

study new therapeutic directions, and the development

of immunotherapy has become a harbinger of the era

of personalized medicine with the deepening of tumor

immunology.

The application of Immune checkpoint inhibitors

(ICIs) is a great leap forward in the immunotherapy of

non-small cell lung cancer, such as antibodies to

CTLA-4 or PD-1 or its death-ligand 1(PD-L1).

Immune checkpoint inhibitors have been developed to

target immune escape and immunosuppression of

tumors (Galluzzi, Zitvogel, Kroemer, 2016). Unlike

chemotherapy or targeted drugs that directly target

malignant cells, immune checkpoint inhibitors are

thought to stimulate immune-associated cell-mediated

immune recognition and clearance, and work by

modulating T-cell function and mechanisms related to

targeted immune resistance, such as

immunosuppressive factors in the tumor

microenvironment. The interaction between PD-1 and

the PD-L1/PD-L2 ligand inhibits T cell proliferation

and promotes the secretion of cytokines related to

immune response. Pd-l1 and PD-L2 ligands are

expressed by antigen-presenting cells (APC) and can

be expressed by tumor cells or other cells in the tumor

microenvironment to promote tumor cell proliferation

(Wang, et al., 2014). It is the monoclonal antibody

against PD-1 or PD-L1 that blocks their interaction

and rejuvenates T cells to eliminate cancer cells. Ctla-

4 is mainly expressed in dendritic cells and inhibits the

activation of CD28-dependent T cells, resulting in

decreased levels of IL-2, IL-4, TNF-α and IFN-γ, and

decreased proliferation of CD8+ and CD4+T cells. In

addition, the interaction of CTLA-4 with CD80 and

CD86 expressed by conventional T cells increases

their inhibition of Treg mediation (Xiao, et al., 2020).

In recent years, targeted therapy has proposed new

treatment options for patients with genetic dysfunction

of NSCLC, but many patients do not have carcinogens

such as epidermal growth factor and anaplastic

lymphoma kinase, and drug resistance is inevitable

(Low, et al., 2019). Approximately 60% of patients

develop primary drug resistance during anti-PD-1

/PD-L1 therapy, and effective patients will also

develop secondary drug resistance as NSCLC patients

receiving targeted therapy. At present about the

resistance mechanism of the immune checkpoint

inhibitors may have the following several aspects:

448

Liu, Y.

Immune Checkpoint Inhibitor Therapy: Application in Non-Small Cell Lung Cancer.

DOI: 10.5220/0012032400003633

In Proceedings of the 4th International Conference on Biotechnology and Biomedicine (ICBB 2022), pages 448-456

ISBN: 978-989-758-637-8

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

first, the effect of T cell activation depends on the local

immune of the tumor microenvironment, first of all,

the cancer cells of the immune cells to identify cancer

cells around, so after lifting immunosuppression, these

identifiable immune cells can effectively play a role of

anti-tumor, i.e. thermal tumor. If the tumor is cold, due

to the low degree of immune resistance in the immune

microenvironment and the immunogenicity of the

tumor itself is lower than that of the thermal tumor,

there will be no immune cells to kill the tumor after

the removal of immunosuppression (Arbour, Riely,

2019). Second, the TMB value of tumors. Studies

have confirmed that low mutation load and poor

immunogenicity of tumors will affect the development

and maturity of effector T cells, affect the activation

of T cells, and lead to the occurrence of drug resistance

(Suresh, et al., 2018). Third, effect closely associated

with APCs and T cell activation antigen presenting

cells, dendritic cells, for example, by taking the tumor

antigens, and to the effect of T cells, a process that

strong induction and activation of the effects of tumor

antigen specific T cells, which mediates antitumor

effect, disrupting any link in the process is likely to

lead to the occurrence of immune resistance. Fourthly,

there are many immunosuppressive pathways in

human body. In addition to pD-1 /PD-L1 signaling

pathway and CTLA-4 signaling pathway, there are

also TIM3 and LAG3, etc. It is assumed that these

immunosuppressive pathways coexist in tumor

tissues. If only one immunosuppressive pathway is

blocked, the other immunosuppressive pathways will

still be normal transduction. Even with compensatory

enhancement, immunotherapy does not achieve ideal

efficacy (Champiat, et al., 2017).

At present, immunotherapy for NSCLC has

achieved good results in phase I /II clinical trials:

improved tumor response rate, small toxic and side

effects, and easy tolerance by patients, which will

develop a new field for NSCLC treatment. Immune

checkpoint inhibitor therapy achieves anti-tumor

effect by inhibiting immune checkpoint activity,

releasing immune brake in tumor microenvironment

and reactivating the immune response effect of T cells

to tumor, which also makes it a new weapon against

tumor. Clinically, some patients can achieve lasting

clinical results and remain free of any tumor-related

clinical symptoms for several years.

This review mainly includes the following parts:

mechanism of action, clinical application, immune

escape mechanism and main adverse reactions of

immune checkpoint inhibitor therapy in non-small cell

lung cancer.

2 MECHANISM OF IMMUNE

CHECKPOINT INHIBITORS IN

THE TREATMENT OF

NON-SMALL CELL LUNG

CANCER

Lung cancer can be divided into primary lung cancer

and secondary lung cancer, according to etiology,

while NSCLC is the most common type of primary

lung cancer. Among them, non-small cell lung cancer

(NSCLC) accounts for about 85% of primary lung

cancers (Brahmer, et al., 2018). The overall five-year

survival rate of lung cancer patients in the past 40

years is still less than 21% (Lu, Yang, Huang, et al.,

2019). Unfortunately, about 60% of patients are

diagnosed at an advanced stage and lose the

opportunity for surgical treatment. The only treatment

options for these patients are chemotherapy,

radiotherapy and targeted therapy. It is reported that

the 5-year survival rate of NSCLC is only 17%, and

the 5-year survival rate of advanced NSCLC is less

than 5% (Siegel, Miller, Jemal, 2017).

Table 1: Basic information on non-small cell lung cancer.

Type Adenocarcinoma Squamous cell carcinomas Large cell carcinoma

Incidence rate About 50% About 30% About 5%

Features

The most common type of

lung cancer, especially in

non-smokers. Targeted

drugs are suitable for most

atients in China.

Squamous cell carcinoma

usually grows slowly.

Surgery is an option for

early detection.

Relatively rare, but

malignant degree is

generally higher, easy to

metastasize.

Metastatic Moderate Moderate Strong

Main treatment

modalities

Surgery, chemotherapy,

radiation, targeted drugs

Surgery, chemotherapy,

radiation

Surgery, chemotherapy,

radiation

Immune Checkpoint Inhibitor Therapy: Application in Non-Small Cell Lung Cancer

449

The body resists tumor formation through

acquired immunity. Tumor cells avoid detection and

attack by the body's immune system through allowing

tumor cells to escape the immune killing impact and

advance to growth and metastasis, according to

immunology. Antigen uptake, processing, and

presentation by antigen-presenting cells start the

immune response. APC binds to major

histocompatibility complex (MHC) molecules and

transfers antigen to the t-cell surface receptor.

Furthermore, T cells' CD28 receptor binds to APC's

CD80/CD86 ligand, causing both signals to activate

T cells (Reck, Heigener, Reinmuth, 2016). As

demonstrated in Figure 1, lung cancer cells'

immunological escape weakens the immune response

primarily through the immune checkpoint pathway,

which includes CTLA-4 and PD-1.

2.1 Anti-CTLA-4 Antibody

CTLA-4 is a CD28 homologous analogue. CTLA-4

is more compatible with CD80/CD86 than CD28,

hence CTLA-4 preemies CD80/CD86 by competitive

action. CTLA-4 can also suppress the production of

CD80 / CD86 on APC or remove it via

cytoendocytosis, preventing CD28 from attaching to

T cells and inhibiting T cell activation (Qureshi,

Zheng, Nakamura, et al., 2011). In the process of T

cell activation and immune response activation,

CTLA-4 acts as a negative regulator. Antibodies

against CTLA-4 can disrupt inhibitory signals,

causing T cells to activate and proliferate, thus

restoring their function.

Fig. 1 T cell activation mechanism and immune checkpoint inhibitor action mechanism.

2.2 Anti-PD-1 /PD-L1 Antibody

PD-1, a type I transmembrane glycoprotein, was first

identified in isolation of mouse T cells involved in

programmed cell death. PD-L1 and PD-L2 are the

two ligands for PD-1. In normal tissues, the

expression of PD-L1 regulates the expression of the

tissue's own immune response after a prolonged

inflammatory response to tissue injury. T cells, B

cells, macrophages, vascular endothelial cells, islet

cells, and other cells all express PD-L1. PD-L2 is

mostly expressed in macrophages and B cells, with a

low level of basic expression (Sharpe, Pauken, 2018).

Tyrosine residues in the cytoplasmic domain are

phosphorylated after PD-L1 interacts to ligands, and

protein-tyrosine phosphatase (PTP) is recruited.

Signal kinases in signaling pathways are

dephosphorylated as a result of this PTP. The signal

transduction of CD28 receptor positive activation is

inhibited (Akinleye, Rasool, 2019). PD-1 signaling

inhibits T cell activation and proliferation by

lowering activating transcription factors (TFs) such

as activating protein 1 (AP1), activating T cells

(NFAT), and NF-κβ (Wu, Gu, Chen, et al., 2019).

3 CLINICAL APPLICATION OF

IMMUNE CHECKPOINT

INHIBITORS IN NON-SMALL

CELL LUNG CANCER

3.1 Immune Checkpoint Inhibitor

Monotherapy

As the rise of immunotherapy and multiple ICI

approved for monotherapy, some studies reported that

CTLA-4 antibodies (Ipilimumab, Tremelimumab)

and human anti-PD-1 / PD-L1 antibodies

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450

(pembrolizumab, Nivolumab, Atezolizumab) was

effective in the treatment of NSCLC in recent years.

Pembrolizumab monotherapy, based on

KEYNOTE024 and 042, is utilized as a first-line

treatment for PD-L1 positive NSCLC patients,

particularly those with high PD-L1 expression (Mok,

Wu, Kudaba, et al., 2019). After the CheckMate 017

and CheckMate 057 studies compared to docetaxel,

nivolumab was authorized for second-line therapy of

advanced relapsed or refractory NSCLC (Borghaei,

Paz-Ares, Horn, et al., 2015). The efficacy of

Atezolizumab in lung cancer was revealed in a Phase

II trial of POP-lar, and this benefit was particularly

pronounced in patients with high PD-L1 expression

(Fehrenbacher, Spira, Ballinger, et al., 2016). The

OAK Phase III experiment was later confirmed.

Regardless of PD-L1 expression status, atezolizumab

was approved for treatment in previously treated

patients with metastatic NSCLC (Brahmer,

Govindan, Anders, et al., 2018).

3.2 Immune Checkpoint Inhibitors

Combined with Chemotherapy

Pembrolizumab plus chemotherapy significantly

improved ORR compared to chemotherapy alone and

pembrolizumab, regardless of PD-L1 expression,

following KEYNOTE 021 first successful

combination of platinum-based chemotherapy with

ICI in patients with advanced NSCLC. The risk of

tumor progression and death was cut in half (Langer,

Gadgeel, Borghaei, et al., 2016), and immunotherapy

was switched to a combination treatment. The

objective response rate of Nivolumab combined with

conventional chemotherapy was as high as 47% in

CheckMate 012

(Rizvi, Hellmann, Brahmer, et al.,

2016), with a 2-year OS rate of 62% for

Nivolumab(5mg/kg) plus paclitaxel-carboplatin.

Pembrolizumab plus pemetrexed and platinum-based

patients with previously untreated metastatic non-

squamous NSCLC without EGFR or ALK mutations

had a median progression-free survival of 8.8 months

in Keynote-189 (Gandhi, Rodriguez-Abreu, Gadgeel,

et al., 2018).

Overall, 69.2% of patients survived for 12

months. IMpower132 found that Atezolizumab in

combination with chemotherapy improved PFS more

than chemotherapy alone, while imPOWER150

found that Atezolizumab in combination with

bevacizumab and standard chemotherapy improved

OS regardless of pD-L1 expression or genetic

changed status of EGFR or ALK (Socinski, Jotte,

Cappuzzo, et al., 2018). In patients with metastatic

non-squamous non-small cell lung cancer who do not

have EGFR or ALK genetic abnormalities, the FDA

has approved Atezolizumab in combination with

bevacizumab and conventional chemotherapy as a

first-line treatment.

3.3 Combination Therapy with

Immune Checkpoint Inhibitors

The CheckMate 012 experiment began attempting

dual ICI medication therapy based on the various

modes of action of the PD-1 and CTLA4 pathways.

In the first-line therapy of NSCLC patients,

Nivolumab plus Ipilimumab has a tolerable safety and

therapeutic effect (Hellmann, Rizvi, Goldman, et al.,

2017). The CheckMate 227 study also found that,

regardless of PD-L1 status, the median PFS in the

dual ICI group (Nivolumab plus Ipilimumab) was 7.2

months compared to 5.4 months in the high-TMB

chemotherapy group. The ORR was also greater, at

45.3% vs. 26.9%. 252 patients with recurrent stage

IIIB/IV NSCLC treated with Nivolumab in

combination with Ipilimumab were divided into three

groups based on pD-L1 expression levels of less than

1%, 1%, and more than 1% in CheckMate 568

(Ready, Hellmann, Awad, et al., 2019). ORR rates

were 15%, 30%, and 41%, respectively, and ORR

increased as TMB increased.

However, in a Phase Ib

trial (NCT02000947) involving 102 patients with

advanced NSCLC who received Durvalumab, an anti-

PD-L1 antibody, and Tremelimumab, an anti-CTLA-

4 antibody, 29 patients (28%) were stopped due to

treatment-related adverse events, and 37 patients

(36%) had treatment-related serious adverse events

(Antonia, Goldberg, Balmanoukian, et al., 2016).

Group according to PD-L1 expression, 118 patients

were separated into two groups (>25% and <25%) in

the phase III clinical trial (NCT02453282). There was

no statistically significant difference in OS and PFS

whether Durvalumab (or Durvalumab +

Tremelimumab) or chemotherapy was given in

addition to the machine (Rizvi, Cho, Reinmuth, et al.,

2018). D + T was administered in combination with

chemotherapy in a Phase Ib trial (NCT02537418),

and 17 of 24 patients with advanced NSCLC achieved

remission, with an ORR of 52.9%. The efficacy of D

+ T combination with platinum therapy will be further

investigated in the ongoing Phase II clinical trial

(NCT03057106) and Phase III trial (NCT02542293).

The trial's primary goal is OS, with secondary

endpoints including PFS, ORR, quality of life, and

safety, with the particular effect yet to be determined.

Immune Checkpoint Inhibitor Therapy: Application in Non-Small Cell Lung Cancer

451

3.4 Immune Checkpoint Inhibitors

Combined with Indoleamine

2,3-dioxygenase 1(IDO-1)

Inhibitors

IDO-1 is a metalloproteinase that can catalyze the

metabolism of tryptophan into canisuric acid. IDO-1

oxidizes tryptophan to N-formylcanisuric acid and

then converts it into catabolites (Prendergast,

Mondal, Dey, et al., 2018). When tryptophan is

consumed, the activity of T-cell-activated kinase

PKC-θ decreases, and the tryptophan catabolites

promote the differentiation of CD4+T cells into Treg

cells by binding to the aromatics receptor, while

limiting the differentiation of CD4+T cells into Th17

cells, inhibiting the immune system (Zhu, Dancsok,

Nielsen, 2019). Multiple quantitative

immunofluorescence was used to measure the levels

of PD-L1, ID-1, B7-H4 and different tumor-

infiltrating lymphocyte (TIL) subtypes in 552 patients

with stage I to IV lung cancer, and the increase of PD-

L1 and ID-1 was consistent with significant B and T

cell infiltration, with limited co-expression (Schalper,

Carvajal-Hausdorf, Mclaughlin, et al., 2017). The

echo-202 / Keynote-037 trial used the IDO-1 inhibitor

EpACa-dostat in combination with Pembrolizumab

in NSCLC, resulting in an ORR of 35% and a DCR

of 60% in 40 assessable patients. The most common

adverse reactions were fatigue (19%), arthralgia

(9%), and elevated AST (9%). E+P was generally

well tolerated and effective in the treatment of

advanced NSCLC (Mitchell, Hamid, Smith, et al.,

2018).

3.5 Immune Checkpoint Inhibitors

Combined with Radiotherapy

Massive radiotherapy can destroy intracellular DNA,

effectively delay tumor metastasis, and reduce local

compression symptoms in patients with advanced

NSCLC; on the other hand, tumor cells killed by

radiotherapy will release a significant number of new

antigens to stimulate the body's immune response. As

a result, immunocheckpoint inhibitors combined with

radiation have emerged as a new effective therapeutic

strategy for advanced NSCLC. Pembrolizumab (0.2

g/kg every 3 weeks) or radiation (8 Gy 3 times)

followed by Pembrolizumab were given to 76 patients

with relapsed metastatic non-small cell lung cancer

(treatment group). The experimental group's ORR

was 36% vs. 18% at 12 weeks, their PFS was 6.6 vs.

about 2 months, and their median overall survival was

15.9 vs. 7.6 months. For patients with PD-L1 negative

tumors, a subgroup study revealed that increasing the

radiation dose was more effective.

The findings

revealed that a small amount of radiation before to

Pembrolizumab treatment improved the therapeutic

outcome (Theelen, Peulen, Lalezari, et al., 2019).

Patients with advanced NSCLC who received

intravenous Pembrolizumab following local ablation

had a median PFS of about 20 months and an overall

mean survival rate of 90.9% at 1 year in the

NCT02316002 study. Pembrolizumab after local

ablation increases PFS without impairing mass of life

in patients with advanced lung cancer, according to a

study (Bauml, Mick, Ciunci, et al., 2019). However,

several issues remain with this treatment, including

the best dose and timing for ICI-related radiation, the

impact of PD-L1 status, and how to incorporate

immune checkpoint inhibitors into these

combinations. More experimental research is needed

to find the best therapy combination.

3.6 Immune Checkpoint Inhibitors

Combined with Targeted Therapy

First-line targeted therapy with tyrosine kinase

inhibitors (TKI) is preferred for sensitive NSCLC

patients with driver gene mutations such as EGFR,

BRAF, ALK, or ROS1. Due to the drug resistance of

targeted therapies, a combination of ICI and TKI was

tested. Although there were some favorable signs in

some subgroups, overall clinical efficacy was poor,

and adverse events were common (Berghoff,

Bellosillo, Caux, et al., 2019). When TKI therapy is

ineffective or the response to TKI drugs is intolerable,

ICI is indicated.

4 IMMUNE ESCAPE AND

IMMUNOSUPPRESSION IN

NSCLC

Immune escape is a major feature of cancer, in which

tumors lose expression of their antigens, negatively

collectively regulate major histocompatibility

complex (MHC) molecules, reduce antigen

presentation ability, do not express effector T

lymphocyte costimulatory molecules or overexpress

molecules that inhibit the activity of these

lymphocytes. In addition, immunosuppressive factors

can be produced by promoting T regulation of

gonorrhoetic cell differentiation (Tregs) and

increasing the number of myeloid suppressor cells

(MDSCs) (Spagnuolo, Gridelli, 2019), expressing

immune checkpoints to inhibit immune cell function,

leading to immune cell failure and apoptosis, and thus

ICBB 2022 - International Conference on Biotechnology and Biomedicine

452

avoiding the host's immune surveillance (Theelen,

Jong, Baas, 2020). The checkpoint signals PD-1 and

CTLA-4 block T cell activation and allow

malignancies to evade the adaptive immune response

(Somasundaram, Burns. 2017).

PD-1 is a negative

costimulatory receptor, mainly expressed on the

surface of activated T cells and belonging to the

CD28 family. After binding with PD-L1 and PD-L2,

the main ligands on T cells or antigen-presenting cells

(APC), PD-1 reduces the activity of T lymphocytes to

avoid being eliminated by the immune system

(Economopoulou, Mountzios, 2018). The CTLA-4

expression on regulatory T cells causes a decrease in

T cell activity and an increase in the system's

immunosuppressive activity.

5 ADVERSE REACTION

ANALYSIS

5.1 Completion of Immunotherapy

During the period of 70 patients receiving

immunotherapy for non-small cell lung cancer, 2

patients were discontinued due to adverse reactions.

One patient died, and the remaining 67 patients

continued treatment. Among the 70 patients, 67

patients were followed up for 6 months, with a

follow-up rate of 95%. Among them, 18 cases

received 2 cycles of treatment, 12 cases received 3

cycles of treatment, 8 cases received 4 cycles of

treatment, 14 cases received 5 cycles of treatment, 6

cases received 6 cycles of treatment, 4 cases received

7 cycles of treatment, and 8 cases received 8 cycles of

treatment (Fu, Wang, 2020).

5.2 Distribution of Species and

Classification

5.2.1 Type Analysis of Adverse Reactions

The incidence rate of anorexia and tiredness

symptoms was 100% (70 instances), which differed

from the findings of Gettinger et al (Gettinger, Horn,

Gandhi, et al., 2004). And could be due to the fact that

there were 70 patients receiving combination

treatment. With a 1% incidence of bad cardiac

reactions, one patient died, demonstrating that while

the incidence of adverse cardiac reactions is modest,

the fatality rate is significant. The other 19 cases had

a 1%-5% incidence of adverse reactions, which were

common adverse reactions to immunotherapy and

had a low incidence.

5.2.2 Distribution of Adverse Reactions

Three patients (4%) had grade 4 adverse events,

including one with liver function injury and another

with fever. All of the patients were given drug

withdrawal, and one of them died as a result of

cardiac complications. There were 17 cases of grade

1-2 adverse reactions (24%), demonstrating that

immunotherapy adverse reactions are uncommon.

Mild adverse reactions were the most common, while

severe adverse reactions were uncommon, although

severe adverse reactions had major repercussions for

patients (Fu, Wang, 2020).

The safety and observable qualities of epidematic-

free treatment have been proven in terms of the types

and amount of adverse reactions, however life-

threatening and life-threatening adverse reactions do

occasionally occur, necessitating medical

intervention (Table 1) (Fu, Wang, 2020).

Table.2: Analysis of adverse reactions to immune checkpoint inhibitor therapy in 70 patients with non-small cell lung cancer

(cases, %) (Fu, Wang, 2020).

Project Level 1 Level 2 Level 3 Level 4 Total

Incidence

rate (%)

Hypothyroidism 2 - - - 2 3

Rash 4 - - - 4 7

Fever 5 - - 1 4 7

Hepatic 5 - - 1 4 7

Interstitial pneumonia 2 2 - - 4 7

Neurotoxicity 1 - - - 1 1

Cardiac toxicity - - - 1 1 1

Loss of appetite and fatigue 70 - - - 70 100

Immune Checkpoint Inhibitor Therapy: Application in Non-Small Cell Lung Cancer

453

5.2.3 Analysis of Adverse Reaction Time

during Treatment

In the first two cycles of combination chemotherapy,

seventy patients with NSCLC experienced anorexia

and fatigue. There was a total of 20 additional adverse

events, with 18 patients (90%) having immune-

related adverse reactions in the first four cycles. All

immune-related side effects occurred within the first

six cycles of treatment, demonstrating that immune

checkpoint inhibitor-related side effects began early

in the drug administration (Fu, Wang, 2020). There

was no link between the duration of medicine and the

outcome (Table 2).

Table.3: Time of adverse reactions to immune checkpoint inhibitor therapy in 70 patients with non-small cell lung cancer

(cases, %) (Fu, Wang, 2020).

Project

The first

cycle

The second

cycle

The thrid

cycle

The fourth

cycle

The fifth

cycle

The sixth

cycle

Hypothyroidism 1 - - 1 - -

Rash - 2 - 2 -

Fever 2 - 1 1 - -

Hepatic injury - 1 2 1 - -

Interstitial

neumonia

- 2 - 1 1 -

Neurotoxicity 1 - - - - -

Cardiac toxicity - - - - 1 -

Loss of appetite

fati

40 30 - - - -

Total 44 35 3 6 2 -

Incidence rate (%) 62 50 4 8 3 -

6 CONCLUSION

Immune checkpoint inhibitors have changed the

treatment landscape of advanced NSCLC, showing

advantages in first-line, second-line and even multi-

line therapy for patients with NSCLC.Despite the fact

that immunotherapy has demonstrated remarkable

efficacy in patients with non-small cell lung cancer,

there are still a number of pressing issues to be

addressed, including the lack of biomarkers that can

predict immunotherapy on their own, the difficulty of

preventing immune-related side effects, and the

emergence of drug resistance. This paper summarized

the mechanism of ICI in NSCLC, clinical application,

immune escape mechanism and the occurrence of

adverse reactions, with the purpose of summarizing

the latest progress of this immunotherapy and making

prospects. Future immunotherapy research for non-

small cell lung cancer should concentrate on

increasing sensitivity to tumor-specific antigens,

developing additional effective targets and more

reliable biomarkers, and balancing efficacy and

toxicity between monotherapy and combination

therapy.

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