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Review
. 2023 Jun 29:11:1158539.
doi: 10.3389/fcell.2023.1158539. eCollection 2023.

Novel chimeric antigen receptor T cell-based immunotherapy: a perspective for triple-negative breast cancer

Peizhen Geng  1 , Yuhua Chi  2 , Yuan Yuan  1 , Maoquan Yang  1 , Xiaohua Zhao  3 , Zhengchun Liu  1 , Guangwei Liu  4 , Yihui Liu  4 , Liang Zhu  5 , Shuai Wang  4
Affiliations
Review

Novel chimeric antigen receptor T cell-based immunotherapy: a perspective for triple-negative breast cancer

Peizhen Geng et al. Front Cell Dev Biol. .

Abstract

Triple-negative breast cancer (TNBC) is highly aggressive and does not express estrogen receptor (ER), progesterone (PR), or human epidermal growth factor receptor 2 (HER2). It has a poor prognosis, and traditional endocrine and anti-HER2 targeted therapies have low efficacy against it. In contrast, surgery, radiotherapy, and/or systemic chemotherapy are relatively effective at controlling TNBC. The resistance of TNBC to currently available clinical therapies has had a significantly negative impact on its treatment outcomes. Hence, new therapeutic options are urgently required. Chimeric antigen receptor T cell (CAR-T) therapy is a type of immunotherapy that integrates the antigen specificity of antibodies and the tumor-killing effect of T cells. CAR-T therapy has demonstrated excellent clinical efficacy against hematological cancers. However, its efficacy against solid tumors such as TNBC is inadequate. The present review aimed to investigate various aspects of CAR-T administration as TNBC therapy. We summarized the potential therapeutic targets of CAR-T that were identified in preclinical studies and clinical trials on TNBC. We addressed the limitations of using CAR-T in the treatment of TNBC in particular and solid tumors in general and explored key strategies to overcome these impediments. Finally, we comprehensively examined the advancement of CAR-T immunotherapy as well as countermeasures that could improve its efficacy as a TNBC treatment and the prognosis of patients with this type of cancer.

Keywords: chimeric antigen receptors; immunotherapy; radiotherapy; triple negative breast cancer; tumor antigens.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Flow of Production of CAR-T Cells. 1. Removal of T cells from patient with cancer. 2. Activation of T cells with anti-CD3 anti-CD28 activation beads, and transduction of activated T cells with CAR construct. 3. Ex vivo expansion of CAR-T cells and removal of activation beads. 4. Administration of lymphodepletion chemotherapy followed by infusion of CAR-T cell product into patients.
FIGURE 2
FIGURE 2
Structural evolution of CARs. A prototypical CAR consists of an extracellular antigen binding scFv (VH and VL regions of antibody linked by a glycine-serine peptide sequence), a flexible spacer or hinge region, a transmembrane domain, and an intracellular CD3ζ activation domain. First-generation CARs contain only a CD3ζ activation domain. Second-generation CARs contain one costimulatory domain (e.g., CD28). Third-generation CARs contain two costimulatory domains (e.g., CD28 and 4-1BB). The fourth- and fifth-generation CARs contain an interleukin expression inducer domain and an interleukin intracellular receptor, respectively. CAR-modified T cells are activated and can efficiently kill tumor cells via binding of the CAR to TAAs on tumor cells independent of MHC.
FIGURE 3
FIGURE 3
CAR Targets and Signaling Pathways Affected by Radiotherapy in Clinical Trial of CAR-T Cell Therapy for TNBC. The combination of targeted tumor antigen CAR-T cell therapy and radiotherapy significantly upregulates ICAM-1 on TNBC cells by activating NF-kB signaling and promoting CD8+T and NK cell infiltration within the tumor. Therefore, it shows strong anti-tumor efficacy.
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