Mesothelin-targeted immunotoxins in Pancreatic Cancer

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

GOAL #1 LMB-100 Combinations. LMB-100 is a next generation recombinant immunotoxin developed by the Pastan Lab (NCI/ LMB) in collaboration with Roche. This RIT binds to the cancer antigen MSLN and delivers a potent bacterial toxin to the cell cytosol. The toxin, a molecularly engineered variant of Pseudomonas exotoxin A, kills cells by irreversibly modifying a critical enzyme in the protein synthesis pathway resulting in a halt in the cell's ability to produce new proteins. This insult triggers apoptosis in many cell types. AIM 1 (on-going): Evaluate efficacy of MSLN-targeted RITs in pancreatic cancer patients. At least 70% of pancreatic adenocarcinomas express the surface antigen MSLN, making these tumors good targets for MSLN-targeted therapies. Based on our previous results, we initiated 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 determine the safety, tolerability and efficacy of the LMB-100 + NAB-paclitaxel combination. This trial received IRB approval in 6/2016 and formally opened for accrual 8/2016. The trial has completed accrual. We described the results for Arm A of the study in our 2020 publication in Clinical Cancer Research. We found that the development of anti-drug antibodies against LMB-100 limits effective treatment to 2 cycles. A second manuscript describing results of Arm B and the immune effects of LMB-100 treatment (with J. Trepel Neckers, L. Cao, R. Donahue) is currently in preparation. Subsequently, we opened a new clinical trial testing combination of LMB-100 with the JAK inhibitor tofacitinib (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). Tofacitinib has been shown by our collaborators (Fitzgerald, Pastan, Onda) to delay anti-drug antibody formation and also to change the immune composition of tumors resulting in increased efficacy of immunotoxin drugs. This trial was closed to accrual 1/2021 and we are currently analyzing the data. Preliminary results were reported at 2021 virtual GI ASCO and ASCO Annual Meeting. AIM 2 (ongoing): Determine whether LMB-100 or other mesothelin-targeted RITs can boost the effect of immune activating drugs. Pancreatic adenocarcinoma produces an immunosuppressive microenvironment. Killing tumor cells with oncolytic viruses or administering anti-tumor vaccines can cause immune activation. Combining these treatments with immune checkpoint inhibitors (ICIs) has been demonstrated to produce anti-tumor immune responses in pre-clinical models of pancreatic cancer. We hypothesize that since LMB-100 uses a bacterial toxin to kill tumor cells, it may also induce immune activation within the pancreatic cancer microenvironment that could be leveraged to induce an anti-tumor immune response in combination with ICIs. Because our immunotoxins bind only to human (hMSLN) and not to native mouse MSLN (mMSLN), completing this project required development of a syngeneic mouse pancreatic cancer cell line expressing hMSLN and a humanized MSLN mouse strain that would not reject these cells. We have developed such a model in collaboration with the CAPR group at Frederick (Serguei Kozlov, Leidos). Experiments using anti-PD1 and anti-CTLA4 therapies in combination with immunotoxin were negative for efficacy in our new pancreas cancer model. A manuscript describing these data was recently accepted for publication in Molecular Cancer Therapeutics. We are currently exploring additional immunotherapy combinations. GOAL #2 Understanding MSLN Signaling. MSLN is the target of many therapeutics being tested in clinical trials. It has previously been shown to increase the aggressiveness of pancreatic cancer. It is unknown whether current anti-MSLN therapies inhibit the pro-tumorigenic signaling by MSLN or whether they are just addressing toxic payloads to tumor cells. AIM 1 (ongoing): Determine a phenotype of MSLN loss in pancreatic cancer cells. We found that loss of MSLN impairs ability to pancreatic cancer cells to establish peritoneal metastasis deposits. MSLN loss impaired the establishment of blood vessels to the new tumor deposits. This data was published in the journal Molecular Cancer Research in 2020. A review examining peritoneal metastasis in pancreas cancer was published in Cancer and Metastasis Reviews. We are continuing to characterize the signaling pathways responsible and are investigating the role of the immune system in MSLN pro-tumorigenic activity. Recently, we incidentally discovered that furin is not required for the processing of mesothelin pre-cursor protein and reported this result in Biochimica et Biophysica Acta- Molecular Cell Research. AIM 2 (ongoing): Determine why MSLN can be detected in the blood of some but not all patients with tumors that make MSLN. We found that elevated concentrations of the two proteins expressed from the MSLN gene locus, MSLN and MPF, are not found in the blood of pancreas cancer patients (with L. Cao). We have identified a model system in mice to determine what happens to MSLN shed from PDAC. Modeling (by C. Peer) of MSLN transit in this system suggests that shed MSLN is trapped within PDAC tumors. We are continuing to investigate the mechanism for this. Manuscript is in preparation.