ZIA BC 011652 (ZIA) | |||
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Title | Mesothelin-targeted immunotoxins in Pancreatic Cancer | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Alewine, Christine | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $664,209 | Project Dates | 00/00/0000 - 00/00/0000 |
Fiscal Year | 2017 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Digestive Diseases (100.0%) |
Pancreas (100.0%) | ||
Research Type | |||
Systemic Therapies - Discovery and Development Systemic Therapies - Clinical Applications |
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Abstract | |||
LMB-100 Combinations (Goal 1) Background: LMB-100 (previously RG7787) is a next generation recombinant immunotoxin (RIT) developed by the Pastan Lab (NCI/ LMB) in collaboration with Roche. This RIT binds to the cancer antigen MSLN 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 (completed). Determine how the combination of RG7787 and NAB-paclitaxel improves anti-tumor efficacy in pre-clinical models. We recently showed that combination of RG7787 with NAB-paclitaxel, a drug FDA approved for the treatment of pancreatic cancer, produced durable complete regressions in a mouse pancreatic cancer model and that this favorable interaction can also be modeled in cell culture and determined mechanism of this interaction. Our manuscript was published in Oncotarget during FY2017, completing this aim. AIM 2 (continuing). Determine whether delivery and efficacy of RG7787 to tumors can be improved by co-administration of an anti-fibrotic drug. Pancreatic adenocarcinoma contains a large volume of stroma that inhibits delivery of anti-cancer therapeutics, provides cytokines that help tumor cells survive under stress, and suppressed anti-tumor immune activation. In FY2016, we continued testing of the anti-fibrotic drug pirfenidone in collaboration with Perwez Hussain (NCI/LHC), but saw no effect on tumor stroma even in an autochthonous model of pancreatic cancer. We have since entered into a collaboration to test an anti-fibrotic/ anti-angiogenesis drug developed by an extramural investigator. Our Intramural/ Extramural Grant application was not approved FY2016 and we resubmitted FY2017. AIM 3 (continuing). Determine whether RG7787 or other mesothelin-targeted RITs can boost the effect of immune activating drugs like checkpoint inhibitors. 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 inhibition has been demonstrated to produce anti-tumor immune responses in pre-clinical models of pancreatic cancer. We hypothesize that since RG7787 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 immune checkpoint inhibition. Because our immunotoxins bind only to human (hMSLN) and not to native mouse MSLN (mMSLN), completing this project requires introduction of a syngeneic mouse pancreatic cancer cell line expressing hMSLN into a mouse strain that will not reject these cells. In FY2016, we created two Panc02 cell lines that stably express hMSLN. To overcome this issue, we initiated a collaboration with the CAPR group at Frederick (Serguei Kozlov, Leidos) to develop two new syngeneic mouse models with limited expression of hMSLN. During FY2017 we have expanded founder lines, validated expression of transgene and ability of hMSLN(+) cells to grow in these mice, and have now established a colony of sufficient size to begin experiments. CAPR has continued to work on the second model and is validating expression in founder mice. AIM 4 (continuing). 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 results from AIM1, we recently 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) in order to |