Immunomodulating Therapies in Breast Cancer—From Prognosis to Clinical Practice

Abstract

The role of the immune system in breast cancer has been debated for decades. The advent of technologies such as next generation sequencing (NGS) has elucidated the crucial interplay between somatic mutations in tumors leading to neoantigens and immune responses with increased tumor-infiltrating lymphocytes and improved prognosis of breast cancer patients. In particular, triple-negative breast cancer (TNBC) has a higher mutational burden compared to other breast cancer subtypes. In addition, higher levels of tumor-associated antigens suggest that immunotherapies are a promising treatment option, specifically for TNBC. Indeed, higher concentrations of tumor-infiltrating lymphocytes are associated with better prognosis and response to chemotherapy in TNBC. An important target within the cancer immune cell cycle is the “immune checkpoint”. Immune checkpoint inhibitors (ICPis) block the interaction of certain cell surface proteins that act as “brakes” on immune responses. Recent studies have shown that ICPis improve survival in both early and advanced TNBC. However, this comes at the price of increased toxicity, particularly immune-mediated toxicity. As an alternative approach, individualized mRNA vaccination strategies against tumor-associated neoantigens represent another promising approach leading to neoantigen-specific immune responses. These novel strategies should help to improve treatment outcomes, especially for patients with triple negative breast cancer.

New and Emerging Targeted Therapies for Advanced Breast Cancer

“…The PD-1/PD-L1 interaction inhibits cytotoxic T cell activation as a regulatory mechanism. A blockade of the PD-1/PD-L1 axis allows for an increase in the activation of cytotoxic T lymphocytes which become available to infiltrate and attack the breast cancer tumor [52,75]. Several monoclonal antibodies have been designed to bind and block the PD-1/PD-L1 axis.…”

“…Specifically, atezolizumab (PD-L1-binding) and pembrolizumab (PD-1-binding) had only minimal impact when used alone against heavily pretreated TNBC patients; however, upon the addition of chemotherapy, both antibodies demonstrated a significant increase in efficacy. Both atezolizumab and pembrolizumab have been approved for use in advanced stage TNBC patients [75,76].…”

“…These antibodies have demonstrated effectiveness against other cancers such as small cell lung cancer; however, they have not been approved for breast cancer. Durvalumab has shown promise in combination with chemotherapy against early-stage TNBC, but has yet to be approved for this use [75].…”

“…Immune checkpoint inhibitors are a novel treatment option for breast cancer and continue to be investigated and improved [52,75].…”

The paradigm shift in treatment from Covid-19 to oncology with mRNA vaccines

“…Previous vaccination strategies in adjuvant settings, against HER2+ self-antigens have shown substantial efficacy in patients with breast cancer [62] , [63] , [64] . However, such an approach is usually weak as immune response as T-lymphocytes have affinity to HER2+ and thus are subject to central tolerance [65] . An ongoing phase I/II trial is being conducted in patients with TNBC and who completed standard of care chemotherapy, where patients are allocated to receive either 8 vaccination cycles of mRNA WAREHOUSE vaccine (containing pre-formulated, shared tumor antigens, non-mutated) or mRNA MUTANOME vaccine (containing individual mutations).…”