Harnessing the immune system in the battle against breast cancer

Abstract

Breast cancer is the most prevalent malignancy in women and the second most common cause of cancer-related death worldwide. Despite major innovations in early detection and advanced therapeutics, up to 30% of women with node-negative breast cancer and 70% of women with node-positive breast cancer will develop recurrence. The recognition that breast tumors are infiltrated by a complex array of immune cells that influence their development, progression, and metastasis, as well as their responsiveness to systemic therapies has sparked major interest in the development of immunotherapies. In fact, not only the native host immune system can be altered to promote potent antitumor response, but also its components can be manipulated to generate effective therapeutic strategies. We present here a review of the major approaches to immunotherapy in breast cancers, both successes and failures, as well as new therapies on the horizon.

Keywords: adoptive transfer; breast cancer; cancer vaccine; cytokines; immunomodulation; immunotherapy; monoclonal antibody; oncolytic virotherapy.

Figure 1

Immune checkpoint inhibitors. A. Normal T-cell activation requires two functional synapses: binding of an antigen-containing MHC molecule with a T-cell receptor and binding of the co-stimulatory molecule CD28 found on T cells with B7, found on antigen-presenting cells. B. CTLA-4 is a co-inhibitory molecule present on normal T cells. Binding of CTLA-4 with B7 inhibits activation of T cells. Blocking antibodies against CTLA-4 prevents its binding with B7, thereby allowing for CD28 interaction with B7 and T-cell activation. C. PD-1 is a co-inhibitory molecule present on normal T cells. Its ligand, PD-L1, is upregulated in cancer cells. Blocking antibodies against either PD-1 or PD-L1 allow for T-cell activation.

Figure 2

General structure of chimeric antigen receptor. The second generation chimeric antigen receptor (pictured) comprises three primary components: a single chain variable fragment (scFV) that recognizes a specific tumor antigen (e.g., HER2), an intracellular co-stimulatory domain (commonly CD28), and the intracellular CD3ζ chain. Third generation CARs may have a second co-stimulatory domain between the second generation co-stimulatory domain and the CD3ζ chain (typically 4-1BBB or OX40).