The Utilisation of Immune Checkpoint Inhibitors in Triple‑Negative

Breast Cancer

Shenling Wang

College of Landscape Architecture, Nanjing Forestry University, Nanjing, China

Keywords: Immune Checkpoint Inhibitors, Triple‑Negative Breast Cancer, Immunotherapy.

Abstract: For several years, surgical intervention and chemotherapy have been employed to address triple-negative

breast cancer (TNBC), a heterogeneous subtype of invasive breast carcinoma. In recent years, FDA has

sanctioned CTLA-4 monoclonal antibodies (mAbs) such as ipilimumab, along with PD-1/PD-L1 mAbs like

pembrolizumab and atezolizumab, for the therapeutic management of multiple solid tumours, prompted by

research on immune checkpoints including CTLA-4 and PD-1/PD-L1. The combination of PD-1/PD-L1

inhibitors with chemotherapy has demonstrated efficacy in the treatment of both early-stage and metastatic

TNBC when immune checkpoint inhibitors (ICIs) are employed. This article compiles the mechanisms of

PD-1/PD-L1 and CTLA-4 as ICIs, along with their research on monotherapy in TNBC. It also discussed how

combination therapies, which include CTLA-4 and PD-1/PD-L1 inhibitors, as well as chemotherapy and

immunomodulatory drugs (ICIs) can be utilised to treat TNBC. A summary of the negative outcomes of

immunotherapy was also provided.

1 INTRODUCTION

Triple-negative breast cancer (TNBC), a

heterogeneous subtype of invasive breast cancer

(BC), does not express the progesterone receptor

(PR), human epidermal growth factor receptor 2

(HER2), or oestrogen receptor (ER). About 15–

25% of all cases of BC are caused by it (Michaels

et al. 2024). Younger women and women of African

or Hispanic heritage are more likely to have TNBC.

Additionally, patients with germline BRCA1

mutations are more susceptible to developing

TNBC (Derakhshan & Reis-Filho 2022). TNBC has

the greatest incidences of relapse and fatality

among breast cancer subtypes and is difficult to

treat because of its high intrusiveness and tendency

for both regional and distant metastases (Liu et al.

2023, Leon-Ferre & Goetz 2023). Since metastatic

TNBC (mTNBC) lacks specific targets, treatment

options are limited, and surgery and cytotoxic

chemotherapy remain the mainstays of therapy

(Zhu et al. 2021). While these therapies offer some

management of TNBC, their long-term

effectiveness is frequently inadequate, particularly

for mTNBC. This correlates with a bleak prognosis,

yielding a median overall survival (OS) of around

12-18 months. (Cao et al. 2021). The use of PARP

inhibitors, together with traditional protein tyrosine

kinase or phosphoinositide 3-kinase inhibitors, does

not significantly enhance OS (Bai et al. 2021).

Thus, it is essential to investigate more potent

TNBC treatment approaches.

With the advancement of immune therapy in the

past few decades, immune-checkpoint inhibitors

(ICIs) have shown impressive effectiveness in the

curative use of several solid tumours that exhibit

resistance to therapy, including gastric cancer, renal

cancer, and hepatocellular carcinoma

(Poniewierska-Baran et al. 2024, Lavacchi et al.

2020, Akbulut et al. 2024). ICIs function by

targeting and blocking immune checkpoints, such

as CTLA-4 and PD-1, from binding to their ligands

on antigen-presenting cells (APCs) or tumor cells.

This enhances T-cell activity, enabling them to

more effectively identify and attack tumor cells

(Iranzo et al. 2022). Most ICIs are monoclonal

antibodies (mAbs), with the most extensively

studied being the CTLA-4 antibody ipilimumab and

the PD-1/PD-L1 antibodies, such as

pembrolizumab (Kwapisz 2021). TNBC has a

comparatively larger tumor mutational burden and

more lymphocyte infiltration than other BC

subgroups. This suggests that TNBC has an

168

Wang, S.

The Utilisation of Immune Checkpoint Inhibitors in Triple-Negative Breast Cancer.

DOI: 10.5220/0014440100004933

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

In Proceedings of the 1st International Conference on Biomedical Engineering and Food Science (BEFS 2025), pages 168-173

ISBN: 978-989-758-789-4

immunological microenvironment and neoantigens

that provide favorable conditions for the application

of ICIs in its treatment (Liu et al. 2023). Research

has found that PD-L1 is overexpressed on the

surface of TNBC cells, making PD-1/PD-L1 a

primary target for ICI development in TNBC (Li et

al. 2021). In the clinical management of TNBC,

there has been enhancement made with both

monotherapy and combination treatments including

anti-PD-1/PD-L1 drugs. For instance, the Food and

Drug Administration (FDA) authorized

pembrolizumab plus nab-paclitaxel as the primary

therapy for mTNBC after the KEYNOTE-355 trial

proved successful. The FDA granted permission to

the combination of pembrolizumab and

chemotherapy for early-stage triple-negative breast

cancer based on the findings of the KEYNOTE-522

study (Jin et al. 2024). Furthermore, clinical studies

have assessed the anti-PD-1 medication

pembrolizumab and the FDA-approved anti-PD-L1

medication atezolizumab, both in conjunction with

chemotherapy (Heeke & Tan 2021). Moreover,

monotherapy has demonstrated durable effects in

advanced mTNBC (Won & Spruck 2020). Although

ICIs have shown promise in treating TNBC, further

improvements are needed in terms of prognosis and

side effects. The use of ICIs in the management of

TNBC was compiled in this overview, with an

emphasis on PD-1/PD-L1 blockers. It discussed

therapeutic strategies involving both ICI

monotherapy and combination therapy, as well as

the associated toxicities of ICIs.

2 IMMUNE-CHECKPOINT

INHIBITORS IN TRIPLE-

NEGATIVE BREAST CANCER

With the advancement of immunotherapy, ICIs have

been widely employed in cancer treatment. T cell

activation is negatively regulated by immunological

checkpoints, which are molecules found in the

immune system. They function as the immune

system’s ‘brakes’, which are crucial for preserving

self-tolerance and avoiding tissue damage (Li et al.

2021). Malignant cells in cancer use immunological

checkpoints to avoid immune monitoring, which

helps them avoid detection and spread (Sutanto et al.

2024). To put it simply, ICIs work by inhibiting these

checkpoints, which reactivate T cells so they can

identify and combat cancer cells (Sutanto et al. 2024).

The two most investigated targets for ICIs in TNBC

at the moment are PD-1/PD-L1 and CTLA-4, with

PD-1/PD-L1 inhibitors receiving more attention.

CD152, another name for CTLA-4, is a

transmembrane protein. Costimulatory receptors

known as CTLA-4 and CD28 are present on the

outermost membrane of T cells, providing activating

and inhibiting secondary signals, respectively. Both

receptors attach to the APC surface’s B7-1/2

(CD80/86). T cells get activated when CD28 interacts

with B7; however, T cells that are activated

additionally produce CTLA-4, which possesses a

higher attraction for B7 than CD28. Consequently,

CTLA-4 often inhibits T cell activation by

transmitting a suppressive signal to T cells prior to

CD28-mediated activation. (Hossen et al. 2023).

CTLA-4 inhibitors prevent CTLA-4 from attaching to

B7, hence promoting CD28’s attachment to B7 and

facilitating T cell activation. Conversely, CTLA-4

inhibitors may impede the internalisation of B7

ligands by APCs, hence augmenting B7 expression

and improving the binding attraction of CD28 to B7

(Wen et al. 2024). In clinical therapy, CTLA-4

inhibitors like ipilimumab are frequently employed to

manage malignant melanoma. However, there are

currently no FDA-approved CTLA-4 inhibitors for

TNBC.

PD-1 is a type I transmembrane protein that is

widely expressed on the surface of activated T cells,

B cells, monocytes, and dendritic cells (Li et al.

2021). The ligands for PD-1 are PD-L1 and PD-L2,

with PD-L1 being upregulated in various solid

tumors. This upregulation suggests a close

relationship between PD-L1 and tumor immune

evasion (Li et al. 2021, Zhang et al. 2023). Tyrosine

residues on PD-1 undergo phosphorylation upon

binding to PD-L1 on antigen surfaces, transmitting

a co-inhibitory signal. This pathway aids cancer

cells in evading immune system identification by

inhibiting the activation and functionality of cells

such as CD8+ T lymphocytes and natural killer

(NK) cells (Zhang et al. 2023). By obstructing this

interaction, antagonists of PD-1/PD-L1 prevent

detrimental signals from being sent and allow T

cells to perform their standard anti-tumor

immunological roles (Sharma et al. 2023). At now,

PD-1/PD-L1 inhibiting agents, including

pembrolizumab, are widely used as primary agents

in the immunotherapy of breast cancer (Zhang et al.

2023). PD-1/PD-L1 has emerged as a significant

target for TNBC immunotherapies due to the fact

that TNBC cells express PD-1 and PD-L1 at high

levels. Monotherapy and combination treatments

utilising PD-1/PD-L1 inhibitors have shown

The Utilisation of Immune Checkpoint Inhibitors in Triple-Negative Breast Cancer

169

significant progress in the medical management of

TNBC. Atezolizumab was authorized by the FDA

in 2019 to treat PD-L1-positive, locally progressed

TNBC or mTNBC that is incurable. The FDA then

authorized pembrolizumab and chemotherapy in

2020 to treat individuals with PD-L1 expression

positive (CPS≥10) who had locally recurrent,

unresectable, or mTNBC (Li et al. 2022). Blockers

of PD-1/PD-L1 and CTLA-4 both obstruct signals

that diminish T cell activation. PD-1/PD-L1

inhibitors reinstate the toxicity of CD8+ T cells,

while CTLA-4 inhibitors primarily influence the

clonal proliferation and migration of CD4+ T cells

(Zhang et al. 2023). Currently, among

immunotherapeutic agents targeting TNBC, ICIs

have emerged as the most effective treatment

options (Wen et al. 2024). Their development holds

promising prospects for the future treatment of

TNBC.

3 THE MONOTHERAPY OF

IMMUNE-CHECKPOINT

INHIBITORS

3.1 Anti-CTLA-4 Therapy

CTLA-4 sends inhibitory signals to active T cells and

conflicts with CD28 for attaching to B7. This action

impacts CD4+ T cell cloned proliferation and

trafficking, inhibits the T cell cycle’s advancement,

and lowers IL-2 production. (Liu et al. 2023). CTLA-

4 inhibitors work by preventing the interaction

between CTLA-4 and B7 on the membranes of

antigen-presenting cells (APCs). This is the major

mechanism by which they influence the immune

system. Thus, they enhance the activation of T cells

and multiplication and enable T cells to perform their

regular immunological tasks by blocking inhibitory

signals (Sutanto et al. 2024). Additionally, CTLA-4

inhibitors can promote the depletion of regulatory T

cells (Tregs), which maintain immune tolerance in the

tumor microenvironment. This depletion enhances

anti-tumor capabilities (Sutanto et al. 2024). In

bladder cancer (BC), CTLA-4 mAbs can also directly

kill CTLA-4+ BC cells by inducing antibody-

dependent cellular cytotoxicity (ADCC) mediated by

tumor-associated macrophages (Zhang et al. 2023).

The CTLA-4 inhibitors most frequently

approved for therapeutic purposes are ipilimumab

and tremelimumab. First investigated in metastatic

melanoma, ipilimumab is a human immunoglobulin

IgG1 mAb that interacts to CTLA-4. It is currently

being evaluated for safety in early-stage breast

cancer patients in the Phase I clinical trial

NCT01502592. Tremelimumab is a human

immunoglobulin IgG2 mAb targeting CTLA-4. The

Phase II clinical trial NCT02527434 assessed the

efficacy of tremelimumab in TNBC and other

cancers, demonstrating that tremelimumab is a

viable treatment option for TNBC (Zhang et al.

2023). According to studies, TNBC has high levels

of CTLA-4 expression, which promotes tumor

immune evasion (Ji et al. 2023). Consequently, this

strategy still has a lot of potential for growth in the

immunotherapy of TNBC, even though there aren’t

any medicines approved by the FDA for anti-

CTLA-4 therapy in TNBC at the moment.

3.2 Anti-PD-1/PD-L1 Therapy

The PD-1 receptor is a member of the CD28

superfamily. It attracts the intracellular phosphatases

when it connects to its ligand PD-L1. Through a

series of events, these phosphatases disable

subsequent effectors of stimulation of T cells, which

eventually results in the death of T cells or apoptosis

(Bullock & Richmond 2024). The connection

between PD-1 and PD-L1 delivers inhibitory signals

to T cells, hindering their activation and enabling

cancer cells to evade immune system identification.

The basis of the inhibitor technique is the use of mAbs

or tiny chemicals to prohibit PD-1 from conforming

to PD-L1/2. This blockage revitalizes the

immunological activity within the tumor

microenvironment (TME) and returns T cells to their

cytotoxic function (Wen et al. 2024).

In BC, both PD-1 and PD-L1 may function as

targets for ICIs, with PD-L1 being particularly

notable due to its high expression in TNBC. The

FDA has currently allowed a number of mAbs that

target PD-1/PD-L1, including durvalumab,

avelumab, pembrolizumab, atezolizumab,

cemiplimab, and nivolumab (Liu et al. 2023). For

the treatment of TNBC, research has primarily

focused on pembrolizumab and atezolizumab.

Based on the findings of the KEYNOTE-522 study,

the FDA has authorized KEYTRUDA

(pembrolizumab) in order to cure of high-risk early-

stage TNBC. It is used as a single-agent adjuvant

medication after surgery (Tarantino et al. 2022).

The FDA previously granted rapid clearance for the

anti-PD-L1 mAb atezolizumab for PD-L1-positive,

unresectable locally advanced TNBC or mTNBC.

But after the follow-up confirmatory stage III

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Impassion131 trial failed to show benefits in OS or

progression-free survival (PFS) when atezolizumab

and paclitaxel were coupled as opposed to

paclitaxel alone, this approval was revoked (Wen et

al. 2024). Even though the FDA has only licensed a

small number of PD-1 or PD-L1 single-agent

treatments for the manegement of TNBC, PD-1/PD-

L1 inhibitors remain to show great promise in

managing TNBC.

4 COMBINATION TREATMENT

4.1 Antibody-Chemotherapy

Combination Treatment

For many years, the standard treatment for TNBC has

been chemotherapy following surgery. Conventional

chemotherapeutic regimens usually consist of taxanes

(AC-T) after cyclophosphamide and anthracycline

(Leon-Ferre & Goetz 2023). Additionally, given that

most TNBC patients harbor BRCA gene mutations,

chemotherapy made up of platinum has been used to

target DNA damage (He et al. 2021). The

introduction of ICIs targeting PD-1/PD-L1 has led to

their use in clinical practice. However, due to the

inherent heterogeneity of TNBC, most patients show

limited response to chemotherapy and ICIs

monotherapy in clinical settings (Li et al. 2022).

With the advancement of ICIs treatment,

combination therapies involving ICIs and

chemotherapy have demonstrated superior

outcomes in clinical trials. The clinical

effectiveness and safety of platinum-based

chemotherapy and ICIs in combination with

chemotherapy for the initial stages TNBC were

indirectly compared in a meta-analysis. The

findings showed that, in comparison to platinum-

based chemotherapy, the use of ICIs in conjunction

with chemotherapy considerably increased the

pathological complete response (pCR) rate and

decreased adverse effects (AEs) in 1647 patients

(He et al. 2021). mTNBC is often treated with

monotherapy, but combination therapy can increase

the objective response rate (ORR) from 10-30% to

63% (Liu et al. 2023). Patients who were selected

at random to receive both pembrolizumab and

chemotherapy during the KEYNOTE-522

experiment showed a noticeably higher pCR rate.

Due to this discovery, the FDA authorized

pembrolizumab with chemotherapy as neoadjuvant

therapy for extremely dangerous, initial stages

TNBC. Following surgery, the patients remained to

receive monotherapy as an adjuvant treatment

(Tarantino et al. 2022). The effectiveness of nab-

paclitaxel monotherapy and atezolizumab in

combination was evaluated in the IMpassion130

study. Patients suffering from advanced TNBC

treated with combination therapy had a better

prognosis than those treated with monotherapy, as

evidenced by the longer median PFS and OS (Liu et

al. 2023). Chemotherapy plus ICIs is more effective

than chemotherapy alone for patients with advanced

TNBC who express PD-L1 (CPS ≥10), according to

a comparison of median OS between

pembrolizumab and chemotherapy and placebo and

chemotherapy in a trial evaluating the treatment of

advanced TNBC. (Liu et al. 2023). Irrespective of

PD-L1 expression conditions, the IMpassion031

study showed that atezolizumab plus neoadjuvant

chemotherapy (NACT) enhanced pCR in the initial

TNBC patients (Jin et al. 2024).

4.2 Combination of Immune

Checkpoint Inhibitor Therapies

Combining therapy is a viable option for TNBC

patients who do not react to immunochemotherapy

since dual checkpoint (CTLA-4 and PD-1/PD-L1)

inhibitors incorporate the benefits of both

monotherapies. The synergistic advantages of this

combined treatment include CTLA-4 mAbs blocking

inhibitory second signals to promote the stimulation

of T cells and reproduction., as well as PD-1/PD-L1

mAbs blocking their binding to enhance immune

activity within the TME (Li et al. 2021). In a study

using a mouse model of TNBC, the effects of

combining antibodies were assessed. The outcomes

demonstrated that combination therapy was more

effective than monotherapy at inhibiting tumor

growth. According to another research, CTLA-4 and

PD-1 mAbs dramatically inhibit tumour growth and

dissemination by augmenting T cell infiltration inside

BCs (Zhang et al. 2023). Multiple preclinical models

have demonstrated that the concurrent use of CTLA-

4 and PD-1 mAbs enhances the inhibitory effect on

tumors compared to monotherapy, indicating that

combination therapy can compensate for the

limitations of single-agent treatment (Geurts & Kok

2023). Clinical studies have assessed the combined

treatment of drugs that block the PD-1/PD-L1 and

CTLA-4 for a number of BC types, including as

metastatic HER2-negative breast cancer, metaplastic

breast cancer (MpBC), and TNBC. A discontinued

stage two clinical study (NCT03982173) for TNBC

examined the combination of the CTLA-4 inhibitor

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171

tremelimumab and the PD-L1 inhibitor durvalumab

(Zhang et al. 2023).

5 IMMUNE-RELATED ADVERSE

EVENTS

The therapeutic management of TNBC has advanced

significantly thanks to ICIs, both alone and in

combination. However, TNBC remains a disease with

a poor prognosis and is often associated with

immune-related adverse events (irAEs). IrAEs

happen when the patient’s healthy cells are

erroneously attacked by the immune system, which is

completely engaged by immunotherapy. This can

result in a variety of adverse events (Wen et al. 2024).

Anemia, diarrhea, limb pain, and trouble breathing

are the most frequent irAEs observed in clinical

studies using CTLA-4 inhibitors only for BC. In

severe cases, fatal complications such as myasthenia

gravis and uremia have been reported (Zhang et al.

2023). According to a meta-analysis, gastrointestinal,

dermatological, thoracic, and respiratory adverse

events (DAEs) are often linked to ICIs blockers. The

incidence of irAEs is also related to gender and age.

In KEYNOTE-522 clinical study for TNBC

treatment, the most common irAEs during the

combination therapy phase of ICIs and chemotherapy

were infusion reactions, thyroid dysfunction, skin

toxicity, and pneumonia. Some of these damages are

irreversible and may potentially affect fertility in

premenopausal patients (Tarantino et al. 2022).

Therefore, the irAEs brought about by ICIs treatment

should not be overlooked, and future efforts should

focus on improving drugs to reduce the impact of

irAEs on patients. In clinical practice, to facilitate the

proper development of tumor immunotherapy

treatment plans and intervention strategies,

physicians need to continuously monitor patients for

symptoms of irAEs and conduct systematic research

on irAEs (Zhang et al. 2023).

6 CONCLUSION

Substantial improvements have been achieved with

the remedy of BC during the course of the previous

several years thanks to the use of ICIs. As a subtype

of invasive BC, TNBC has long lacked targeted

therapies. However, immunotherapy has become a

viable therapeutic option as our understanding of the

molecular and immunological features of TNBC has

grown. The TME, tumor vaccines, immunotherapy,

integrated traditional Chinese and Western medicine

therapies, and innovative medicines such cell cycle

inhibitors and DNA damage response inhibitors are

the main areas of current research on TNBC

therapeutics. CTLA-4 inhibitors have been widely

used in solid tumors such as metastatic melanoma, but

there are currently no FDA-approved

immunotherapies specifically for TNBC. TNBC

cancer cells frequently overexpress PD-1/PD-L1,

which makes it a more researched target for

immunotherapy. Currently, the FDA has authorised

the utilisation of the PD-1 inhibitor pembrolizumab

plus chemotherapy for clinical management of TNBC

patients. This combination therapy overcomes the

limitations of ICIs or chemotherapy alone and has

improved clinical response rates. However, studies

have shown that TNBC patients generally do not

respond well to ICIs monotherapy.

The research is ongoing for combination

therapies involving ICIs with chemotherapy,

radiotherapy, gene therapy, nanotechnology, and

dual checkpoint inhibitors, offering hope for more

effective TNBC treatments in the future. The

combined effort of immunotherapy and

chemotherapy is regarded as the most successful

medication for TNBC; nonetheless, it is linked to

increased immunotoxicity compared to

chemotherapy alone and may induce numerous

irAEs.Treating TNBC remains a significant

challenge. Future research on ICIs combination

therapies will need to focus on addressing immune

deficiencies and side effects to minimize the harm

of drugs to patients. Additionally, exploring more

immunosuppressive targets, new biomarkers, and

novel drugs is expected to improve the cure rate and

prognosis for TNBC.

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