Eli Gilboa, Ph.D.
Professor of Microbiology & Immunology; Director, Dodson Interdisciplinary Immunotherapy Institute
Description of Research
The goal of the Gilboa lab 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 lab 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, notably b secreting TGF.The Gilboa lab is developing ways to render the vaccine-induced immune cells resistant to the inhibitory effects of TGF by using aptamer to target siRNA to the immune cells that inhibit key steps in the TGF signaling pathway. Using similar platform technology the lab is developing strategies to promote long term antitumor immunological memory, and to recruit the humoral response to control tumor growth.
- Development of mRNA transected 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
- Berezhnoy A, Castro I, Levay A, Malek TR, Gilboa E. Aptamer-targeted inhibition of mTOR in T cells enhances antitumor immunity. J Clin Invest :,2013 [JIF 12.812] Read more »
- Gilboa E, McNamara J 2nd, Pastor F. Use of oligonucleotide aptamer ligands to modulate the function of immune receptors. Clin Cancer Res 19:1054-62,2013 [JIF 7.837] Read more »
- Gilboa E. Expression of new antigens on tumor cells by inhibiting nonsense-mediated mRNA decay. Immunol Res 57:44-51,2013 Read more »
- Pastor F, Soldevilla MM, Villanueva H, Kolonias D, Inoges S, de Cerio AL, Kandzia R, Klimyuk V, Gleba Y, Gilboa E, Bendandi M. CD28 aptamers as powerful immune response modulators. Mol Ther Nucleic Acids 2:e98,2013 Read more »
- Berezhnoy A, Stewart CA, McNamara Ii JO, Thiel W, Giangrande P, Trinchieri G, Gilboa E. Isolation and Optimization of Murine IL-10 Receptor Blocking Oligonucleotide Aptamers Using High-throughput Sequencing. Mol Ther 20:1242-50,2012 [JIF 6.873] Read more »
- Blankenstein T, Coulie PG, Gilboa E, Jaffee EM. The determinants of tumour immunogenicity. Nat Rev Cancer 12:307-13,2012 [JIF 37.545] Read more »
- Pastor F, Kolonias D, McNamara Ii JO, Gilboa E. Targeting 4-1BB Costimulation to Disseminated Tumor Lesions With Bi-specific Oligonucleotide Aptamers. Mol Ther 19:1878-86,2011 [JIF 7.149] Read more »
Leader of the Multidisciplinary Research Program: Tumor Immunobiology Program