Intratumoral injection of checkpoint antibodies and TLR ligands cures established distant tumors in mice, including aggressive spontaneous breast cancers
Idit Sagiv-Barfi, Debra K. Czerwinski and Ronald Levy
Division of Oncology, Stanford University, Stanford, CA
Background: Toll-like receptors (TLRs) are components of the innate immune system that recognize molecular patterns on bacterial, fungal, or viral pathogens. Intratumoral (IT) injection of unmethylated CG-enriched oligodeoxynucleotide (CpG), a TLR9 agonist, results in local tumor eradication but on its own is not able to induce a systemic anti-tumor immune response. OX40 is a potent costimulatory receptor activation conventional T cells, but can also inhibit or kill T regulatory cells by ADCC. In previous preclinical studies OX40 agonists increased antitumor immunity.
Scientific question: Does local injection of CpG and anti-OX40 agonistic antibody trigger a systemic anti-tumor immune response?
Results: We implanted A20 tumors bilaterally in opposite sides of the abdomen. After tumors were established we administered microgram quantities of CpG and anti-OX40 antibody into one of the tumors. This treatment resulted in both a local and an abscopal effect on the contralateral, untreated tumor. In addition, the animals were protected from a second tumor challenge. To examine the potential of this maneuver to treat spontaneous cancers, we chose the mouse tumor model MMTV-PyVT. These animals all develop invasive breast cancer in all of their mammary glands by 12 weeks of age. Injections of CpG and anti-OX40 antibody into the first arising tumor not only prevented its growth but significantly reduced the incidence and outgrowth of subsequent tumors at un-injected mammary glands, reduced the number of lung metastases and improved survival.
Impact: Our results suggest that CpG and anti-OX40 induce fully protective and curative anti-tumor immune responses, even in spontaneously arising cancer. Anti-OX40 and CpG are both currently in phase-I trials as single agents. Our results provide the rationale for testing these agents clinically, injected locally in low doses to induce therapeutic anti-cancer immunity.