Eli Gilboa, Ph.D.
Professor of Microbiology & Immunology; Director, Dodson Interdisciplinary Immunotherapy Institute
Description of Research
The goal of the Tumor Immunobiology Program is to develop a combination of clinically compatible approaches to enhance the antigenicity and immunogenicity of the disseminated tumor lesions of the cancer patient by targeting immune modulatory agents to the tumor and the immune system, essentially converting the tumor lesions into pathogens (immunologically speaking of course). To this end, the Program is developing short nucleic acid-based immune modulatory agents with complementary mode of action that are targeted to the tumor cells or the tumor activated immune system of the patient using oligonucleotide aptamer ligands. Cell targeting will reduce the risk of toxicity associated with immune modulation, and the chemically synthesized oligonucleotides offer enhanced feasibility to generate and test multiple clinical grade immune modulatory agents.
A main reason why tumors are not controlled by the immune systems is that, unlike pathogens, they don’t express potent tumor antigens. To enhance tumor antigenicity Dr. Gilboa and his colleagues are developing an approach to express new antigens in tumor cells using aptamer targeted RNAi to inhibit the nonsense mediated mRNA decay (NMD) process in tumor cells. In mice, aptamer-targeted delivery of NMD factor specific siRNAs corresponding to NMD factors led to significant inhibition of tumor growth which was superior to that of vaccination with a best-in-class vaccination protocol in mice. A second reason why tumors evade the immune system is the paucity of costimulation at the tumor site which compromises the survival and proliferative capacity of the tumor infiltrating T cells. To this end, Dr. Gilboa and his colleagues are targeting costimulatory ligands to tumor cells in situ using bi-specific aptamer conjugates. In murine studies, systemic delivery of an agonistic 4-1BB aptamer ligand conjugated to a PSMA-binding tumor-targeting aptamer led to inhibition of tumor growth, was more effective than, and synergized with, vaccination, and exhibited a superior therapeutic index compared to costimulation with 4-1BB antibodies. Tumors have also elaborated immune suppressive strategies comprised of immune suppressive cell types such as foxp3-expressing regulatory T cells (Treg), or immune suppressive mediators such as TGFβ or IL-10. To counter tumor-induced suppression Dr. Gilboa’s team is developing methods to inactivate Treg using aptamer targeted foxp3 siRNA; and to confer resistance to TGFβ inhibition they are using aptamers to target activated T cells with siRNAs corresponding to components of the TGFβ signaling pathway. Using similar platform technology the are developing strategies to promote long term antitumor immunological memory, and to recruit the humoral response to control tumor growth.
Highlights
- Development of mRNA transfected dendritic cell-based vaccines which engender potent antitumor immunity in murine tumor models and stimulate immune responses in clinical trials
- Inducing antitumor immunity by immunizing against products expressed in the tumor stroma as a way to limit immune escape of tumors
- Development of oligonucleotide aptamers that block the immune inhibitory function of CTLA-4 and promote the immune potentiating functions of 4-1BB and OX40
- Development of a method to express new antigens in tumor cells in situ by tumor targeted inhibition of nonsense-mediated mRNA decay using aptamer-siRNA conjugates
- Development of a method to promote costimulation at the tumor site using bi-specific aptamer conjugates
Selected Cancer-Related Publications
- Zhou J, Soontornworajit B, Martin J, Sullenger BA, Gilboa E, Wang Y. A hybrid DNA aptamer-dendrimer nanomaterial for targeted cell labeling. Macromol Biosci 9:831-5,2009. Read more »
Programs
Leader of the Multidisciplinary Research Program: Tumor Immunobiology Program