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.