Precision Therapy to Target Pancreatic Ductal Adenocarcinoma

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

GOAL A (ongoing)- Role of MSLN in PDAC. MSLN is the target of many therapeutics being tested in clinical trials, including LMB-100 but little is understood about the effect of MSLN on PDAC aggressiveness and therapeutic resistance. We have previously found that loss of MSLN impairs the ability of PDAC to colonize the peritoneum and cause metastasis there. MSLN loss from cancer cells impaired the establishment of blood vessels to the new tumor deposits. In FY23, we are specifically investigating whether shed MSLN is responsible for increased metastatic efficiency or whether membrane-bound MSLN is more important in metastasis promotion. Importantly, our previous work has been performed with human PDAC cell lines using immune-suppressed mice as hosts. However, MSLN has previously been shown to interact with macrophages in the immune system and can be recognized by tumor-fighting lymphocytes in the peripheral blood of PDAC patients. In collaboration with Serguei Kozlov (NCI/CAPR), we developed new immune-competent PDAC models with MSLN loss to better understand the role of MSLN in this context. During FY23 we have continued to investigate the pathways contributing to PDAC metastasis in these models. We hope to submit our work for publication during FY24. GOAL B (clinical trial complete, data analysis ongoing)- LMB-100/ tofacitinib clinical testing. The clinical study "A Phase I Study of Mesothelin-Targeted Immunotoxin LMB-100 in Combination with Tofacitinib in Persons with Previously Treated Pancreatic Adenocarcinoma, Cholangiocarcinoma and other Mesothelin Expressing Solid Tumors" (PI Alewine) was closed to accrual in 1/2021 due to toxicity and our results have been published in abstract form at national meetings. We are continuing to analyze the results of correlative studies examining the patient immune response to treatment. Manuscript submission is anticipated late FY23 or FY24. GOAL C (complete)- Patient immune response to LMB-100 treatment. We analyzed patient blood samples collected during accrual of "A Phase Ib/II Study of Mesothelin-Targeted Immunotoxin LMB-100 in Combination with Nab-Paclitaxel in Participants with Previously Treated Metastatic and/ or Locally Advanced Pancreatic Ductal Adenocarcinoma" (PI Alewine) to identify cytokine and immune cell changes that accompany 1) patient response to treatment, and 2) significant capillary leak syndrome (the dose-limiting toxicity of LMB-100/ nab-paclitaxel combination). We found that the patient who achieved an objective response to iTox treatment had large increases in immune cells that can fight cancer following the treatment, while other patients did not. Moreover, patients who would go on to develop significant capillary leak syndrome had increases in specific cytokines within hours of LMB-100 administration suggesting that this toxicity was caused by immune response to the iTox. These findings were published in the journal Cancer Medicine in 2023. GOAL D (newly initiated)- Developing a MSLN-targeted nanoboady drug conjugate (NDC). Mitchell Ho (NCI/ LMB) has recently engineered a high affinity nanobody against MSLN that is much smaller than traditional antibodies. We are collaborating with chemist Goncalo Bernardes (Cambridge) to conjugate this nanobody with a payload for therapeutic use against PDAC. GOAL E (newly initiated)- TGF-beta modulation to remodel the PDAC tumor microenvironment. We are collaborating with HCW Therapeutics to test the safety of HCW9218, a novel protein drug with dual TGF-beta antagonist activity and IL-15 agonist activity. We are actively enrolling patients on this first-in-human clinical trial.