Exploring Immunotherapy Options for Breast Cancer

This slideshow provides an overview of immunotherapy approaches being used and studied in the treatment of breast cancer.

Breast Cancer Immunotherapy

Immune Checkpoint Blockade

Pembrolizumab is currently the only FDA-approved immunotherapy for breast cancer, used in early and metastatic triple-negative breast cancer (TNBC), with PD-L1 testing in the metastatic setting.

Pembrolizumab and nivolumab are immune checkpoint inhibitors (ICIs) that target PD-1 to prevent T-cell exhaustion; atezolizumab and durvalumab target PD-L1 to block tumor-mediated immune evasion; and ipilimumab targets CTLA-4 to enhance T-cell priming.1-3

The addition of ICB therapy to chemotherapy increases the chance of a pathologic complete response (pCR) and event-free survival (EFS) in patients with early-stage TNBC.

References

FDA.gov. Accessed April 30, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-high-risk-early-stage-triple-negative-breast-cancer

Mittendorf EA et al. Lancet. 2020 Oct 10;396(10257):1090-1100. doi:10.1016/S0140-6736(20)31953-X.

Emens L et al. J Immunother Cancer. 2021 Aug;9(8):e002597. doi:10.1136/jitc-2021-002597.

Immune checkpoint blockade (ICB) is a cancer immunotherapy that inhibits checkpoint proteins (PD-1, PD-L1, CTLA-4), which can act as brakes on the immune system. ICB blocks these checkpoints, reactivating T cells to recognize and destroy tumor cells.

Immune Checkpoints

CTLA-4 (cytotoxic T-lymphocyte–associated antigen 4) is a protein receptor found on the surface of T cells, particularly regulatory T cells (Tregs) and activated T cells and downregulates T cell activation.

PD-L1 (programmed death-ligand 1) binds to PD-1 and acts as an “off switch” for the immune system.

Reference

Emens L et al. J Immunother Cancer. 2021 Aug;9(8):e002597. doi:10.1136/jitc-2021-002597.

PD-1 promotes apoptosis (programmed cell death) of antigen-specific T-cells in lymph nodes and reduces apoptosis in regulatory T cells (eg, anti-inflammatory, suppressive T cells).

Peptide Immunotherapy

The Flamingo-01 phase 3 trial is testing a HER2/neu peptide vaccine that targets the GP2 epitope and is combined with GM-CSF, which acts as an adjuvant to boost the immune response.

Peptides have displayed high specificity, high tissue penetration, and reduced toxicity, along with the ability to regulate key pathways in breast tumor, including HER2, VEGF, and EGFR.

References:

Peptide-based vaccines and immune-modulating peptides have demonstrated the ability to enhance anticancer immunity. Vaccines under study are being used to deliver tumor-specific peptides (epitopes) to prime the immune system, often including adjuvants such as GM-CSF (granulocyte-macrophage colony-stimulating factor) and TLR (toll-like receptor) agonists to enhance immune activation and stimulate a T-cell response against cancer cells.

Peptides in nanoparticles have provided improved delivery of drugs and genes in studies.

Personalized neoantigen peptides are derived from patient-specific tumor mutations and are created after tumor sequencing and HLA typing. They can be used to create custom vaccines or to expand T cells ex vivo, as in TIL (tumor-infiltrating lymphocyte) therapy. They are still in the experimental stage but hold promise for TNBC.

Alai E et al. Pathol Res Pract. 2025 May:269:155946. doi:10.1016/j.prp.2025.155946.

Peptide immunotherapies use short chains of amino acids (peptides) derived from tumor-associated antigens (TAAs) to stimulate the immune system, especially cytotoxic T cells (CD8⁺), to recognize and destroy cancer cells.

Patel S et al. J Clin Oncol. 2024 Jun; 42:16(suppl). https://doi.org/10.1200/JCO.2024.42.16_suppl.TPS617.

Abdou Y et al. NPJ Breast Cancer. 2022 Nov 9;8:121. doi:10.1038/s41523-022-00486-y.

Adoptive TIL therapy is based on isolation of TILs from the tumor environment, ex vivo activation and expansion with the help of high-doses of interleukin-2 (IL-2), and then infusion back into the patient. TIL effectiveness has been measured for all breast cancer subtypes, with early-phase clinical trials being undertaken for metastatic TNBC and HER2-negative breast cancer.

Adoptive Immunotherapy

CARs can recognize a wide range of cell surface antigens, including glycolipids, carbohydrates, and proteins derived from tumors in a non−MHC-restricted manner, which helps overcome MHC downregulation as a mechanism of tumor escape. Several clinical trials are ongoing for breast cancer treatment.

Retecki K et al. Cancers (Basel). 2021 Nov 29;13(23):6012. doi:10.3390/cancers13236012.

In adoptive cell therapy (ACT), a patient’s immune cells are collected, modified or expanded outside the body, and then reinfused to enhance the immune system’s ability to fight cancer. ACTs include the adoptive transfer of tumor-infiltrating lymphocytes (TILs), dendritic cells, natural killer (NK) cells, and T/NK cells that are genetically modified to express CAR (chimeric antigen receptors ) molecules, as well as engineered T cell receptors.

Choi Y et al. Int J Mol Sci. 2025 Apr 21;26(8): 3920. https://doi.org/10.3390/ijms26083920.

In NK cell–based therapy, NK cells from donors or the patient are expanded or engineered (eg, CAR-NK cells). Targets include HER2 and EpCAM. Early-phase trials are ongoing for TNBC and HER2-low tumors.

References:

When considering metastatic sites to test for PD-L1, it is preferable to prioritize extrahepatic sites or the primary tumor, if available.

Society of Immunotherapy Guidelines

Immunotherapy regimens for stage II or III TNBC should at least include an anthracycline and a taxane with or without carboplatin.

For patients with high-risk, early-stage TNBC, pembrolizumab plus chemotherapy is used as neoadjuvant treatment, and then pembrolizumab is used as a single agent as adjuvant treatment after surgery.

All patients with advanced TNBC should have tumor tissue tested for PD-L1, TMB (tumor mutational burden), and MSI (microsatellite instability).

For MSI-H/dMMR (microsatellite instability−high/deficient mismatch repair) or TMB-high (tumor mutational burden) solid tumors with progression on prior treatment, pembrolizumab is recommended at a dosage of 200 mg every 3 weeks or 400 mg every 6 weeks).

In locally recurrent/metastatic TNBC with a PD-L1 combined positive score (CPS) of 10 or more by the 22C3 assay, pembrolizumab (200 mg every 3 weeks or 400 mg every 6 weeks) plus chemotherapy is recommended.

For patients with stage II and III TNBC, improved pathologic complete response (pCR) rates with either neoadjuvant pembrolizumab or atezolizumab have been observed, regardless of PD-L1 status.

Reference:

Emens L et al. J Immunother Cancer. 2021 Aug;9(8):e002597. doi:10.1136/jitc-2021-002597.

Myositis: It is important to recognize IR myositis and monitor for myocardial involvement, as well as bulbar involvement, which may rapidly lead to cardiac or respiratory failure, persistent disability, or even death.

ESMO Guidelines on
Immunotherapy Side Effects

Diabetes mellitus: For new-onset IR DM, prompt insulin initiation is warranted. Patients presenting with ketoacidosis should be admitted to the hospital.

Dyspnea: Dyspnea should trigger a full clinical workup, including the exclusion of infectious pneumonia, tumor progression, pulmonary embolism, cardiac events (including heart failure, myocarditis, acute myocardial infarction, and arrhythmias) and pleural carcinomatosis or effusion.

Skin: Immunotherapy-related cutaneous adverse events (ircAEs) are the most common side effects of ICI therapy (>50%). Patients with corticosteroid (CS)-refractory ircAEs may benefit from cytokine inhibitors. Rare, severe ircAEs, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous lesions, and DRESS syndrome (drug reactions with eosinophilia and systemic syndrome), necessitate immediate interruption of ICI therapy.

Myocarditis: Patients suspected of having IR myocarditis should be admitted to level 2 or 3 care with electrocardiogram monitoring and resuscitation facilities.

Liver injury: Because of the potential for IR liver injury, assessment of serum transaminases, alkaline phosphatase, and bilirubin before every cycle of ICI therapy is recommended.

Hypo/hyperthyroidism: In IR hypothyroidism greater than grade 2, hormone replacement therapy (levothyroxine, 50-100 μg/day) should be started in symptomatic cases, and the dose should be increased over several weeks until thyroid-stimulating hormone (TSH) levels normalize. ICI therapy should be interrupted only if symptoms are severe (grade ≥3). In symptomatic IR hyperthyroidism (grade ≥2), ICI therapy should be interrupted, and beta-blocker therapy should be started.

Reference:

Hannen J et al. Ann Oncol. 2022 Dec;33(12):1217-1238. doi:10.1016/j.annonc.2022.10.001.

Inflammatory arthritis: Prednisone 10-20 mg/day should be initiated in cases of IR inflammatory arthritis and IR polymyalgia rheumatica of grade 2 or more, and then progressively tapered following improvement.

Note: ESMO is the European Society of Medical Oncology (ESMO). Grades of severity follow the Common Terminology Criteria for Adverse Events created by the National Cancer Institute. The grades range from 1 (mild) to 5 (death related to adverse event).

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Rebecca Shover

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