Immunotherapy in breast cancer

Abstract

The idea of using the immune system to fight cancer is over 100 years old. A new molecular approach led to a better understanding of the immune system. Checkpoint regulation, understanding the roles of Tregs, Th1, and Th2, development of Chimeric antigen receptor (CAR)-T cells, as well as regulation of dendritic cells and macrophages, are just a few examples of our understating that has also led to the discovery of immune checkpoint inhibitors (ICIs) and modulators. This led the Nobel Prize committee in 2018, to award Dr. James P. Allison the Nobel Prize in medicine for the discovery of Cytotoxic T-lymphocyte-associated antigen-4, and Dr. Tasuku Honjo for the discovery of programmed cell death-1 (PD-1)/PD-1-ligand (PDL-1). Several ICIs are already approved by the regulatory authorities, and many more are currently used in studies of several solid tumors and hematologic malignancies. Positive studies have led to the US Food and Drug Administration (FDA) and European Medicines Agency approval of a number of these compounds, but none to date are approved in breast cancer (BC). Moreover, PD-1/PDL-1, MSI high (and dMMR), and tumor mutational burden are the currently "best" predictive markers for benefit from immunotherapy. BCs have some of these markers positive only in subsets but less frequently expressed than most other solid tumors, for example, malignant melanoma or non-small cell lung cancer. To improve the potential efficacy of ICI in BC, the addition of chemotherapy was one of the strategies. Many early and large clinical trials in all phases are underway in BC. We will discuss the role of immune system in BC editing, and the potential impact of immunotherapy in BC outcomes.

Keywords: Breast cancer; checkpoint inhibitors; cytotoxic T-lymphocyte-associated antigen-4; immunotherapy; programmed cell death ligand-1; programmed cell death-1.

Figure 1

Immune system functions and components relevant to breast cancer therapy[95]

Figure 2

Co-stimulatory and co-inhibitory receptors expressed by T-cells (green) and target cells (rose). Reproduced with permission from Schutz F. et al. PD-1/PD-L1 pathway in Breast Cancer, Oncol Res Treat 2017

Figure 3

The general architecture of a chimeric antigen receptor consists of a single-chain variable fragment derived against a predetermined tumor-associated antigen followed by a CD3ζ domain required for provision of signal 1 and T-cell activation upon antigen recognitionBayraktar