Combination Therapy of T-Cell Engager and Chemotherapy for Pancreatic Cancer Treatment

Abstract public domain (NIH RePORTER)

The American Cancer Society estimates that in 2025 approximately 67,440 new cases of pancreatic cancer will be diagnosed in the United States, with 51,980 deaths. Nearly 80% of patients present with locally unresectable or metastatic disease, where the 5-year survival rate is as low as 3%. Standard first-line regimens—FOLFIRINOX (5- FU, leucovorin, irinotecan, oxaliplatin) and gemcitabine plus nab-paclitaxel (Abraxane)—achieve median overall survival (mOS) of up to 21 months, yet outcomes remain dismal, underscoring the urgent need for novel therapeutic strategies. Advances in antibody engineering have enabled bispecific antibodies (BsAbs) that engage T cells and redirect them toward tumors. In our prior Phase I awards, we developed a panel of BsAb T-cell engagers and identified MUCD3 as the lead candidate. Preclinical studies demonstrated that MUCD3 slowed tumor growth as monotherapy and, when combined with Abraxane and gemcitabine, significantly inhibited chemotherapy-resistant pancreatic tumors. Importantly, the combination also reduced cytokine release, a common limitation of T-cell engagers. In this Phase II SBIR proposal, we will advance MUCD3 through key preclinical studies designed to de-risk its path toward first-in-human (FIH) trials and eventual commercialization. MUCD3, produced from Lonza-generated stable cell pools, will first be evaluated for structural stability in mouse serum at 37 °C, followed by pharmacokinetic studies in HuCD34-NSG and FcRn mice to guide dosing strategies. Efficacy will be assessed in four tMUC1- positive patient-derived xenograft (PDX) orthotopic models spanning a range of expression levels. In parallel, cytokine release assays in human samples and a maximum tolerated dose (MTD) study in non-human primates will establish the safety margin of MUCD3 in combination with nab-PTX and gemcitabine. These animal models are essential to evaluate the in vivo pharmacokinetics, tumor-targeting efficacy, and safety of MUCD3 within an intact biological system, which cannot be fully replicated using in vitro approaches. We will collaborate with Dr. Tim Pardee (Atrium Health Wake Forest Baptist), Dr. Michael Morse (Duke Health), and Dr. Mohamed Salem (Levine Cancer Institute, Atrium Health), whose expertise in clinical oncology and trial design will guide execution of these studies and the design of the FIH trial. We anticipate that MUCD3, combined with Abraxane and gemcitabine, will demonstrate enhanced efficacy with reduced toxicity compared to current chemotherapy, offering the potential to meaningfully improve survival and quality of life for pancreatic cancer patients

Public health relevance public domain (NIH RePORTER)

Narrative Pancreatic cancer is one of the deadliest cancers, with very limited treatment options and survival rates that remain extremely poor. To address this urgent medical need, OncoTAb has developed a new therapy that uses the patient’s own immune system to fight cancer. This treatment is based on a specially engineered protein that directs immune cells to recognize and kill pancreatic cancer cells. Since the protein targets tMUC1, a marker present on more than 80% of pancreatic cancers, it has the potential to help most patients. Our early studies have shown that this therapy can slow tumor growth on its own and, when combined with chemotherapy, may also help treat tumors that resist standard treatment. In this Phase II SBIR project, we will perform additional laboratory studies and work with oncologists to prepare for the first clinical trial of this promising therapy in pancreatic cancer patients.