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Dian-Jang Lee, Ph.D., D.V.M.

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Biography
National Taiwan University, Taipei, TaiwanDVM
Ludwig Maximilian University of Munich, Munich, GermanyPhDPharmacy
2017
AbbVie PhD Prize
2017
Biotechnology Graduate Student Research Award
2017
Oskar-Karl-Forster Scholarship
2016 - 2017
Best Manuscript in Physical Pharmacy and Biopharmaceutics
2016
Jan Feijen Poster Prize

Overview
Recent immune-oncology (I-O) clinical trials have shown dramatic, durable responses in melanoma, renal cell carcinoma, lymphoma, leukemia, uroepithelial and non-small cell lung cancer. The goal of immune therapy is to counteract tumor editing that selects for tumors resistant to immune surveillance and activate dysfunctional immune cells that have evolved to tolerate the tumor. The most successful current immune therapies use checkpoint inhibitors to restore functionality to exhausted tumor-infiltrating lymphocytes (TIL) or adoptively transferred, genetically engineered cytotoxic T cells expressing chimeric receptors (CAR T cells) that target tumor cells for elimination.

However, most cancers, even in responsive cancer types, do not respond to checkpoint inhibitors. Much of the ongoing work to improve response rates focuses on combinations of checkpoint inhibitors, with some, mostly incremental, successes, but with the risk of increased autoimmune toxicity, because checkpoint inhibitors remove the brakes on all T cells, not just anti-tumor T cells. Increasing the response rate for I-O therapies will require new strategies that directly address the main problem (lack of tumor recognition by T cells), potentially used in combination with conventional chemotherapy, new targeted therapies or checkpoint inhibitors.

We aim to develop a new platform that can both evaluate new I-O targets in solid tumors and be used as tumor-targeted I-O drugs. We will evaluate new strategies to make aggressive cancers visible to the immune system and counteract T cell exhaustion. To accomplish this goal, we will knockdown genes selectively in cancer cells, but not in normal tissue. Immune modulation of the cancer cell should be largely free of autoimmune side effects. We have adapted an effective method for in vivo tumor-targeted gene knockdown that uses RNA aptamers (which can be thought of as RNA “antibodies”) - structured RNAs that bind with high affinity to a cell receptor - to deliver covalently linked small interfering RNAs (siRNAs) into cells. Knockdown occurs selectively in receptor-bearing cells when aptamer-siRNA chimeras are internalized and cleaved intracellularly to liberate an active siRNA. EpCAM, the first described tumor antigen, is expressed at several logs higher levels in epithelial cancers (97% of breast cancers, 100% of lung, pancreas, colon, ovarian, prostate cancers) and their “cancer stem cells” than normal epithelia, making it an attractive target for selective tumor targeting. For tumor targeting, we use an EpCAM aptamer that binds with low nanomolar affinity to both mouse and human EpCAM.

Our main goal is to identify novel strategies/drug targets to induce or restore anti-tumor immunity in solid tumors. As a corollary, another goal is to develop a useful platform to knockdown genes in vivo (with minimal off-target effects) in epithelial tumor cells, including the small populations of aggressive cancer stem cells. This platform could be used to investigate the in vivo importance of individual tumor dependency or immune modulating genes or to define the role of specific gene products on tumor biology or anti-tumor immunity. By the end of this grant, we will have identified individual EpCAM-AsiCs that could also serve as candidate immune modulatory drugs for preclinical evaluation.

Bibliographic
Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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PMC Citations indicate the number of times the publication was cited by articles in PubMed Central, and the Altmetric score represents citations in news articles and social media. (Note that publications are often cited in additional ways that are not shown here.) Fields are based on how the National Library of Medicine (NLM) classifies the publication's journal and might not represent the specific topic of the publication. Translation tags are based on the publication type and the MeSH terms NLM assigns to the publication. Some publications (especially newer ones and publications not in PubMed) might not yet be assigned Field or Translation tags.) Click a Field or Translation tag to filter the publications.
  1. Zhang Y, Xie X, Yeganeh PN, Lee DJ, Valle-Garcia D, Meza-Sosa KF, Junqueira C, Su J, Luo HR, Hide W, Lieberman J. Immunotherapy for breast cancer using EpCAM aptamer tumor-targeted gene knockdown. Proc Natl Acad Sci U S A. 2021 03 02; 118(9). PMID: 33627408.
    Citations: 2     Fields:    Translation:HumansAnimals
  2. Lee DJ, Wagner E. Combinatorial siRNA Polyplexes for Receptor Targeting. Methods Mol Biol. 2019; 1974:83-98. PMID: 31098997.
    Citations:    Fields:    Translation:HumansCells
  3. Klein PM, Kern S, Lee DJ, Schmaus J, Höhn M, Gorges J, Kazmaier U, Wagner E. Folate receptor-directed orthogonal click-functionalization of siRNA lipopolyplexes for tumor cell killing in vivo. Biomaterials. 2018 09; 178:630-642. PMID: 29580727.
    Citations: 6     Fields:    Translation:HumansAnimalsCells
  4. Lee DJ, Kessel E, Lehto T, Liu X, Yoshinaga N, Padari K, Chen YC, Kempter S, Uchida S, Rädler JO, Pooga M, Sheu MT, Kataoka K, Wagner E. Systemic Delivery of Folate-PEG siRNA Lipopolyplexes with Enhanced Intracellular Stability for In Vivo Gene Silencing in Leukemia. Bioconjug Chem. 2017 09 20; 28(9):2393-2409. PMID: 28772071.
    Citations: 4     Fields:    Translation:HumansAnimalsCells
  5. Krzyszton R, Salem B, Lee DJ, Schwake G, Wagner E, Rädler JO. Microfluidic self-assembly of folate-targeted monomolecular siRNA-lipid nanoparticles. Nanoscale. 2017 Jun 08; 9(22):7442-7453. PMID: 28530287.
    Citations: 4     Fields:    Translation:HumansCells
  6. Klein PM, Reinhard S, Lee DJ, Müller K, Ponader D, Hartmann L, Wagner E. Precise redox-sensitive cleavage sites for improved bioactivity of siRNA lipopolyplexes. Nanoscale. 2016 Oct 27; 8(42):18098-18104. PMID: 27734055.
    Citations: 4     Fields:    Translation:HumansAnimalsCells
  7. Lee DJ, He D, Kessel E, Padari K, Kempter S, Lächelt U, Rädler JO, Pooga M, Wagner E. Tumoral gene silencing by receptor-targeted combinatorial siRNA polyplexes. J Control Release. 2016 12 28; 244(Pt B):280-291. PMID: 27287890.
    Citations: 6     Fields:    Translation:HumansAnimalsCells
  8. Lee DJ, Kessel E, Edinger D, He D, Klein PM, Voith von Voithenberg L, Lamb DC, Lächelt U, Lehto T, Wagner E. Dual antitumoral potency of EG5 siRNA nanoplexes armed with cytotoxic bifunctional glutamyl-methotrexate targeting ligand. Biomaterials. 2016 Jan; 77:98-110. PMID: 26584350.
    Citations: 7     Fields:    Translation:HumansAnimalsCells
  9. Lee DJ, Wagner E, Lehto T. Sequence-defined oligoaminoamides for the delivery of siRNAs. Methods Mol Biol. 2015; 1206:15-27. PMID: 25240883.
    Citations:    Fields:    Translation:HumansAnimalsCells
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Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.