CAR-T cell therapy in triple-negative breast cancer: Hunting the invisible devil

Abstract

Triple-negative breast cancer (TNBC) is known as the most intricate and hard-to-treat subtype of breast cancer. TNBC cells do not express the well-known estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expressed by other breast cancer subtypes. This phenomenon leaves no room for novel treatment approaches including endocrine and HER2-specific antibody therapies. To date, surgery, radiotherapy, and systemic chemotherapy remain the principal therapy options for TNBC treatment. However, in numerous cases, these approaches either result in minimal clinical benefit or are nonfunctional, resulting in disease recurrence and poor prognosis. Nowadays, chimeric antigen receptor T cell (CAR-T) therapy is becoming more established as an option for the treatment of various types of hematologic malignancies. CAR-Ts are genetically engineered T lymphocytes that employ the body's immune system mechanisms to selectively recognize cancer cells expressing tumor-associated antigens (TAAs) of interest and efficiently eliminate them. However, despite the clinical triumph of CAR-T therapy in hematologic neoplasms, CAR-T therapy of solid tumors, including TNBC, has been much more challenging. In this review, we will discuss the success of CAR-T therapy in hematological neoplasms and its caveats in solid tumors, and then we summarize the potential CAR-T targetable TAAs in TNBC studied in different investigational stages.

Keywords: T-cell therapy; adoptive cell therapy; cancer immunotherapy; chimeric antigen receptor; solid tumors; triple-negative breast cancer.

Figure 1

An overall presentation of the CAR-T-targeted TNBC-associated antigens evaluated in different investigational stages.

Figure 2

The structure of a CAR and its five generations. CARs are the result of meticulous protein engineering. The targeting domain of CARs is usually derived from the single-chain fragment variable (scFv) of a monoclonal antibody. scFvs are made from the variable light chain (V_L) and variable heavy chain (V_H) of a monoclonal antibody fused together through a synthetic linker peptide. A spacer called hinge connects the targeting domain of CARs to their transmembrane domain, which connects the ectodomain to the endodomain. Currently, the endodomain of CARs consists of one or two costimulatory domains and an activation domain. An interleukin expression inducer domain and an interleukin intracellular receptor are also located on the endodomain of the fourth- and fifth-generation CARs, respectively. Of note, the first-generation CARs lacked a costimulatory domain which led to their inadequate in vivo persistence and weak antitumor responses. CAR, chimeric antigen receptor; Co-S, costimulatory domain; IL, interleukin; ITAM, immunoreceptor tyrosine-based activation motif; mAb, monoclonal antibody; scFv, single-chain fragment variable; TCR, T-cell receptor; TM, transmembrane domain.

Figure 3

The major impediments of CAR-T therapy in solid tumors. (A) CAR-Ts encounter tumor cells only a proportion of which express the CAR-redirected target antigen. Moreover, in a population of tumor cells, there might be malignant cells not expressing any known target antigens. (B) The immunosuppressive nature of the TME suppresses CAR-T antitumor activity. (C) The extracellular matrix of solid tumors is the most important physical barrier between the tumor cells and CAR-Ts in CAR-T therapy of solid tumors. Cancer-associated fibroblasts are among the mediators responsible for the formation of the stroma extracellular matrix. CAF, cancer-associated fibroblast; CAR-T, chimeric antigen receptor T-cell; DC, dendritic cell; EMC, extracellular matrix; NK, natural killer cell; PD-1, programmed death-1; TAM, tumor-associated macrophage; TME, tumor microenvironment.