Abstract A130: LOKI-101-001: Phase 1, open-Label, first-in-human trial of intraperitoneal Lm-LLO-TT and gemcitabine in participants with unresectable pancreatic ductal adenocarinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer mortality in the US, is poorly immunogenic, and novel therapies to enhance anti-cancer immune activity are urgently needed. In our previously published preclinical studies, tetanus toxoid (TT) protein was cloned into an attenuated variant of the bacterium Listeria monocytogenes as a fusion protein, designated Lm-LLO-TT. Transgenic KPC and syngeneic Panc02 mouse models of PDAC harboring orthotopic and metastatic tumors were given two TT vaccinations to establish anti-tetanus memory T cells, followed by intraperitoneal (IP) Lm-LLO-TT alternately with low doses of gemcitabine (GEM) (60 mg/kg IP). Lm-LLO-TT accumulated in tumors and metastases with the highest concentrations on days 1 and 3. There was limited accumulation of Lm-LLO-TT in normal tissues, reflecting selective accumulation of Listeria to the tumor. Lm-LLO-TT + GEM resulted in significant improvement in the survival of mice with advanced PDAC (7.3 vs 5 months, p<0.0001), decreased tumor size (80%, p<0.01), and fewer metastases (87%, p<0.01). Tumor tissue revealed increased CD4 T cells attracted to the TME of transgenic KPC mice, producing high levels of Perforin and Granzyme B. Overall, Lm-LLO-TT led to strong anti-tumor activity, activation of memory T cell response against TT, and encouraging safety profile in preclinical models of PDAC, warranting clinical investigation. In a tumor with well documented immunosuppression in the TME like PDAC, Lm-LLO-TT employs a unique strategy to use participants' existing immune response to tetanus toxoid to mount a potent tumor-localized immune response. Loki Therapeutics has initiated a phase 1 dose escalation trial. The key inclusion criteria are participants age >18, histology proven PDAC with measurable disease on imaging, and at least one prior line of systemic therapy. Primary objective is to assess safety, MTD, and RP2D of IP Lm-LLO-TT + GEM. Secondary endpoints include determination of objective response rate based on RECIST v1.1, DCR, and 6-month PFS. All participants will receive a TT booster during screening. A peritoneal port will be placed for IP injections of Lm-LLO-TT and GEM. Dose escalation will follow a Bayesian Optimal Interval design with 3 dose levels: 2x10^7 CFU/kg, 1x10^8 CFU/kg, and 5x10^8 CFU/kg. The study will enroll 9-18 participants. A full treatment cycle will include a high dose of Lm-LLO-TT on day 1, followed by multiple low doses of GEM (180 mg/m2) alternating with low doses of Lm-LLO-TT (1x10^6 CFU/kg). Exploratory correlative studies will include immune markers in pre- and post-treatment tumor biopsies, circulating tumor DNA dynamics, and immune cell profiling. The first round of GMP manufacturing of Lm-LLO-TT has been completed. Study approval has been granted by the U.S. Food & Drug Administration under IND 32753. Study startup is underway at Montefiore Einstein Comprehensive Cancer Center, with anticipated study activation date of 8/14/2026 and first participant in on 8/19/2026.