Emerging Immunotherapies against Novel Molecular Targets in Breast Cancer

Abstract

Immunotherapy is a highly emerging form of breast cancer therapy that enables clinicians to target cancers with specific receptor expression profiles. Two popular immunotherapeutic approaches involve chimeric antigen receptor-T cells (CAR-T) and bispecific antibodies (BsAb). Briefly mentioned in this review as well is the mRNA vaccine technology recently popularized by the COVID-19 vaccine. These forms of immunotherapy can highly select for the tumor target of interest to generate specific tumor lysis. Along with improvements in CAR-T, bispecific antibody engineering, and therapeutic administration, much research has been done on novel molecular targets that can especially be useful for triple-negative breast cancer (TNBC) immunotherapy. Combining emerging immunotherapeutics with tumor marker discovery sets the stage for highly targeted immunotherapy to be the future of cancer treatments. This review highlights the principles of CAR-T and BsAb therapy, improvements in CAR and BsAb engineering, and recently identified human breast cancer markers in the context of in vitro or in vivo CAR-T or BsAb treatment.

Keywords: CAR-T; TNBC; bispecific antibodies; breast cancer; immune checkpoints; immunotherapy; mRNA vaccine; precision therapy; triple-negative breast cancer; tumor specific/associated antigens.

Figure 1

The Normal CD8+ T Cell Response. Infected cells will process and present a portion of the viral or bacterial protein on major histocompatibility complex (MHC) Class 1 molecules. The T cell receptor (TCR) on CD8+ T cells will recognize this antigen bound to MHC. The CD8 co-receptor helps with recognition of MHC Class I. Upon TCR/CD8 co-receptor binding, the intracellular CD8 and CD3ζ domain work together to produce activation signal 1. Additionally, a costimulatory signal involving B7 and CD28 is required in order to promote T cell activation, cytokine production, and prevention of anergy and apoptosis. Upon cytotoxic T cell activation, the T cell releases perforin and granzyme, which act upon the infected cell to initiate the extrinsic apoptosis pathway.

Figure 2

The Chimeric Antigen Receptor T cell (CAR-T Cell). The chimeric antigen receptor (CAR) construct is inserted into T cells and enables initiation of apoptosis via binding to tumor-specific or tumor-associated antigens independent of MHC interaction. Part of the figure adapted from “Chimeric Antigen Receptor (CAR)” and “CAR-Engrafted T cell and Tumor Cell”, by BioRender.com (2021). Retrieved from https://app.biorender.com/biorender-templates (accessed on 28 February 2021).

Figure 3

Bispecific antibodies. Bispecific antibodies (BsAbs) bind to the tumor target of interest and induce T cell activation, localization to tumor, and polyclonal proliferation by simultaneous interaction with the T cell’s CD3 domain (A). The bispecific antibody’s function arises from its ability to bind two separate antigens (A). Various bispecific antibody structures exist as illustrated (B,C). Part A of the figure adapted from “Bispecific Antibody Design”, by BioRender.com (2021). Retrieved from https://app.biorender.com/biorender-templates (accessed on 28 February 2021).

Figure 4

Mechanism of mRNA vaccine utilized in cancer therapeutics and COVID-19 prevention. The mRNA containing the coding sequence for the target protein is protected by lipid nanoparticles in order to ensure proper delivery to cells (1). Once the mRNA is inside cells, the intracellular machinery will translate the mRNA into the protein of interest (2). Then, this protein is processed as a foreign invader, which enables portions of the protein (antigens) to be presented on MHC class I by nucleated cells or class 2 by antigen presenting cells (3). MHC class I presentation generates killing of the cell as well as clonal expansion of the CD8+ T cell (4). MHC class II presentation induces the CD4+ helper T cell-dependent amplification of the immune response by further activating T cells and antibody secreting B cells (4). This mechanism, popularized by the recent invention of COVID-19 vaccines, has been previously utilized in cancer immunotherapy.