Intratumoral injection of TLR9 agonist promotes an immunopermissive microenvironment transition and causes cooperative antitumor activity in combination with anti-PD1 in pancreatic cancer

Background Complex tumor and immune\r\nmicroenvironment render pancreatic ductal\r\nadenocarcinoma (PDAC) resistant to immune checkpoint\r\ninhibitors (ICIs). Therefore, a strategy to convert the\r\nimmune hostile into an immunopermissive tumor is\r\nrequired. Recent studies showed that intratumoral\r\ninjection of Toll-like\r\nreceptor 9 agonist IMO-2125 primes\r\nthe adaptive immune response. Phase I and II trials with\r\nintratumoral IMO-2125 demonstrated its safety and\r\nantitumoral activity.\r\nMethods We generated an array of preclinical models\r\nby orthotopically engrafting PDAC-derived\r\ncell lines in\r\nsyngeneic mice and categorized them as high, low and\r\nno immunogenic potential, based on the ability of tumor\r\nto evoke T lymphocyte or NK cell response. To test the\r\nantitumor efficacy of IMO-2125 on locally treated and\r\ndistant sites, we engrafted cancer cells on both flanks of\r\nsyngeneic mice and treated them with intratumoral IMO-\r\n2125 or vehicle, alone or in combination with anti-PD1\r\nICI.\r\nTumor tissues and systemic immunity were analyzed by\r\ntranscriptomic, cytofluorimetric and immunohistochemistry\r\nanalysis.\r\nResults We demonstrated that intratumoral IMO-2125\r\nas single agent triggers immune system response to kill\r\nlocal and distant tumors in a selected high immunogenic\r\nsubtype affecting tumor growth and mice survival.\r\nRemarkably, intratumoral IMO-2125 in combination with\r\nsystemic anti-PD1\r\ncauses a potent antitumor effect on\r\nprimary injected and distant sites also in pancreatic cancer\r\nmodels with low immunogenic potential, preceded by a\r\ntransition toward an immunopermissive microenvironment,\r\nwith increase in tumor-infiltrating\r\ndendritic and T cells in\r\ntumor and lymph nodes.\r\nConclusion We demonstrated a potent antitumor activity\r\nof IMO-2125 and anti-PD1\r\ncombination in immunotherapy-resistant\r\nPDAC models through the modulation of immune\r\nmicroenvironment, providing the rationale to translate this\r\nstrategy into a clinical setting.