Multifunctional Nanovaccine Sensitizes Breast Cancer to Immune Checkpoint Therapy

Breast cancer is the primary cause of cancer-related death in women worldwide. Breast cancer subtypes are characterized by different gene expression patterns, which drive their prognostic factors and therapeutic options. Among them, triple-negative breast cancer (TNBC) is one of the deadliest due to its aggressiveness, high rate of early recurrence and distant metastases, and limited therapeutic options. Despite the recent approval of monoclonal antibodies targeting programmed cell death protein 1 (PD-1) or its ligand (PD-L1) for the treatment of TNBC patients with a locally recurrent unresectable or metastatic tumor expressing PD-L1, their response rate is very modest. It is reported that polymeric nanoparticle (NP)-based cancer vaccines, co-entrapping tumor-associated antigens, Toll-like receptor ligands and small interfering RNA (siRNA) targeting the expression of the immunosuppressive cytokine transforming growth factor (TGF)-beta 1 by dendritic cells, sensitized TNBC to the agonist immune checkpoint OX40, inhibiting tumor growth and increasing overall survival. This anti-tumor immune-mediated effect is also observed in a luminal type of mammary cancer similar to human disease. Therefore, these synergistic anticancer effects of alpha OX40 and the antigen-specific adaptive immunity induced by nanovaccine-mediated TGF-beta silencing may guide the development of novel combination regimens able to improve the response rate to this aggressive tumor. A biodegradable multifunctional PLA-based vaccine designed to co-deliver in vivo breast cancer-associated antigens (alpha-Lac and KRAS), TLR ligands (CpG and Poly(I:C)) and siRNA TGF-beta 1 to dendritic cells and tumor microenvironment (TME) induce a strong anti-tumor immune-mediated effect and sensitize the triple-negative and luminal B-like breast cancers to the agonist immune checkpoint OX40, inhibiting tumor growth and increasing overall survival. image