PIP-CpG consists of a TLR9 agonist (CpG) conjugated to a synthetic, ultra-stable, and disulfide-rich peptide with strong affinity for multiple tumor-associated integrins. PIP-CpG retains TLR9 agonistic activity and is capable of binding human, rat, mouse, and non-human primate integrins. Systemic delivery of PIP-CpG to mice was well tolerated, localized to the spontaneously metastasizing and poorly immunogenic tumor 4T1, reduced immunosuppressive MDSC within the TME, induced regression of both 4T1 and KPC-G2 tumors, increased lymphocyte infiltration and activation, and elicited T cell-mediated tumor-specific immune responses.
Contributed by Margot O’Toole
ABSTRACT: Promoting immune activation within the tumor microenvironment (TME) is a promising therapeutic strategy to reverse tumor immunosuppression and elicit anti-tumor immunity. To enable tumor-localized immunotherapy following intravenous administration, we chemically conjugated a polyspecific integrin-binding peptide (PIP) to an immunostimulant (Toll-like receptor 9 [TLR9] agonist: CpG) to generate a tumor-targeted immunomodulatory agent, referred to as PIP-CpG. We demonstrate that systemic delivery of PIP-CpG induces tumor regression and enhances therapeutic efficacy compared with untargeted CpG in aggressive murine breast and pancreatic cancer models. Furthermore, PIP-CpG transforms the immune-suppressive TME dominated by myeloid-derived suppressor cells into a lymphocyte-rich TME infiltrated with activated CD8+ T cells, CD4+ T cells, and B cells. Finally, we show that T cells are required for therapeutic efficacy and that PIP-CpG treatment generates tumor-specific CD8+ T cells. These data demonstrate that conjugation to a synthetic tumor-targeted peptide can improve the efficacy of systemically administered immunostimulants and lead to durable anti-tumor immune responses.
Author Info: (1) Department of Bioengineering, Stanford University, Stanford, CA 94305, USA. (2) Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305, USA. (3)
Author Info: (1) Department of Bioengineering, Stanford University, Stanford, CA 94305, USA. (2) Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305, USA. (3) Department of Medicine, Stanford University, Stanford, CA 94305, USA; Department of Biochemistry, Stanford University, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA. (4) Department of Chemistry and Stanford ChEM-H, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA. (5) Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA. Electronic address: jennifer.cochran@stanford.edu.
