Current status and innovative developments of CAR-T-cell therapy for the treatment of breast cancer

Abstract

Breast cancer will overtake all other cancers in terms of diagnoses in 2024. Breast cancer counts highest among women in terms of cancer incidence and death rates. Innovative treatment approaches are desperately needed because treatment resistance brought on by current clinical drugs impedes therapeutic efficacy. The T cell-based immunotherapy known as chimeric antigen receptor (CAR) T cell treatment, which uses the patient's immune cells to fight cancer, has demonstrated remarkable efficacy in treating hematologic malignancies; nevertheless, the treatment effects in solid tumors, like breast cancer, have not lived up to expectations. We discuss in detail the role of tumor-associated antigens in breast cancer, current clinical trials, barriers to the intended therapeutic effects of CAR-T cell therapy, and potential ways to increase treatment efficacy. Finally, our review aims to stimulate readers' curiosity by summarizing the most recent advancements in CAR-T cell therapy for breast cancer.

Keywords: Breast cancer; CAR T cells; CAR signaling; In vivo studies; T cell exhaustion; T cell persistence.

Fig. 1

Chimeric Antigen Receptor (CAR) T cell Therapy. The extracellular domain of CARs uses the scFv, which is derived from the variable region of antibodies, to identify tumor antigens on the surface of tumor cells. A transmembrane (TM) domain connects the extracellular and intracellular regions of CARs, as well as one or more costimulatory domains that cause a longer T-cell activation and cytokine-mediated killing of tumor cells

Fig. 2

CAR T cell causing cancer cell death. The interaction of TAA with the CAR results in the production of granzymes, perforin, IL-2, INF-α, and TNF-α, which cause tumor cells to undergo apoptosis. This interaction occurs independently of the MHC I antigen

Fig. 3

Downstream pathways activation of TNBC tumor associated with TGFβ, and HER2/EGFR. The stimulation of downstream signaling pathways, including PI3K/AKT, Ras/MEK/ERK, PLCγ/PKC, and JAK/STAT, is a crucial factor in the development of tumors [42]. Cell migration, survival, proliferation, and death are all regulated by the PI3K/AKT signaling system. Cell survival, migration, and proliferation are governed by the pathways of Ras/MEK/ERK and PLCγ/PKC, whereas the JAK/STAT system governs angiogenesis and metastasis. HER2 and EGFR are two RTK that have been linked to abnormal expression or hyperactivation in breast cancer [42]. Because HER2 signaling is triggered by somatic mutations in the HER2 gene, these mutations also aid in the development of breast cancer

Fig. 4

Tumor extracellular matrix reduces therapeutic efficiency in solid tumors. The tumor microenvironment (TME) comprises all components of a tumor. Of these components, the extracellular matrix (ECM) is the least well studied. Solid tumors induce high expression of ECM molecules (collagens, proteoglycans, hyaluronic acid and laminins), which become complex and disordered, resulting in altered characteristic. Here the ECM acts as a physical barrier, reducing the delivery of therapeutics, nutrients, and immune cells to solid tumors, and leading to poorer prognosis

Fig. 5

Challenges for CAR-T cell immunotherapy for solid tumour. Several challenges for CAR T cell immunotherapy for solid tumors are still existing including tumor heterogeneity, antigen escape, insufficient ability of CAR T cells for trafficking & infiltration of solid tumor environment, and the immunosuppressive & nutrients restrictive tumor environment