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IntroductionImmunotherapies have shown great promise, but are not effective for all tumors types and are effective in less than 3% of patients with pancreatic ductal adenocarcinomas (PDAC). To make an immune treatment that is effective for more cancer patients and those with PDAC specifically, we genetically engineered Salmonella to deliver exogenous antigens directly into the cytoplasm of tumor cells. We hypothesized that intracellular delivery of an exogenous immunization antigen would activate antigen-specific CD8 T cells and reduce tumors in immunized mice. MethodsTo test this hypothesis, we administered intracellular delivering (ID) Salmonella that deliver ovalbumin as a model antigen into tumor-bearing, ovalbumin-vaccinated mice. ID Salmonella delivers antigens by autonomously lysing in cells after the induction of cell invasion. ResultsWe showed that the delivered ovalbumin disperses throughout the cytoplasm of cells in culture and in tumors. This delivery into the cytoplasm is essential for antigen cross-presentation. We showed that co-culture of ovalbumin-recipient cancer cells with ovalbumin-specific CD8 T cells triggered a cytotoxic T cell response. After the adoptive transfer of OT-I CD8 T cells, intracellular delivery of ovalbumin reduced tumor growth and eliminated tumors. This effect was dependent on the presence of the ovalbumin-specific T cells. Following vaccination with the exogenous antigen in mice, intracellular delivery of the antigen cleared 43% of established KPC pancreatic tumors, increased survival, and prevented tumor re-implantation. DiscussionThis response in the immunosuppressive KPC model demonstrates the potential to treat tumors that do not respond to checkpoint inhibitors, and the response to re-challenge indicates that new immunity was established against intrinsic tumor antigens. In the clinic, ID Salmonella could be used to deliver a protein antigen from a childhood immunization to refocus pre-existing T cell immunity against tumors. As an off-the-shelf immunotherapy, this bacterial system has the potential to be effective in a broad range of cancer patients.
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Screening of Polymeric Gels As A Means Of Controlling Local Skin Delivery
Introduction: Skin Cancer is the most common cancer by which people are afflicted. While most forms of skin cancer have high survival rates if they are caught early, both Squamous Cell Carcinoma and Melanoma can metastasize and are very difficult to treat once this happens. Matrix Metallopeptidases (MMPs), Normally involved in cell growth, movement, and death, can become overactive in patients with cancer. While research suggested that MMP inhibitors could be used to treat many forms of cancer, clinical trials in late stage cancer patients showed that this was not the case. While they were not useful in shrinking late stage tumors, they were effective in preventing growth and metastasis of existing tumors. For this reason, they may be especially useful in the treatment of skin cancers as they may prevent metastasis. While MMP inhibitors can be delivered systemically, whether orally, or intravenously, systemic delivery can give rise to severe unwanted off-target side effects. As such, localized delivery is preferable. By incorporating MMP inhibitors into polymer gels, the drug can be administered topically and its distribution within the skin and into the systemic circulation may be controlled. Formulations may therefore be customized to alter the depth which the drug is delivered.
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- Award ID(s):
- 1757885
- PAR ID:
- 10138550
- Date Published:
- Journal Name:
- 2019 BMES Conference Proceedings - REU Abstract Accepted Poster
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Accepted Manuscript1.0
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