Our Faculty : Primary Faculty

Eli Gilboa, Ph.D.

Background
Dr. Eli Gilboa Ph.D. received his Ph.D. in molecular biology at the Weizmann Institute, Rehovot, Israel, was an assistant professor in the Department of Molecular Biology at Princeton University from 1980-1986, and served as an associate member of the Memorial Sloan-Kettering Institute from 1986-1993. In 1993 Dr. Gilboa joined Duke University Medical Center as the Joseph and Dorothy Beard Professor of Experimental Surgery and Immunology and Director of the Center for Genetic and Cellular Therapies overseeing the development and clinical implementation of novel gene- and cell-based therapies. Dr. Gilboa made numerous contributions in the fields of gene therapy, developing the first generation of retroviral vectors, including the widely used “self inactivating” vectors, HIV research, rendering immune cells genetically resistant to HIV using “TAR decoys”, and cancer immunotherapy, developing mRNA transfected dendritic cell based vaccines. In 2006 Dr. Gilboa joined the Sylvester Comprehensive Cancer Center and the Department of Microbiology & Immunology, Miller School of Medicine, University of Miami as the Joe Enloe Dodson Professor of Microbiology & Immunology and Director of the Dodson Interdisciplinary Immunotherapy Institute. The current research in the Gilboa lab is focused on developing a combination of complementary and synergistic cell-targeted immune stimulatory strategies using short nucleic acid based therapeutic agents, such as siRNAs or microRNAs, conjugated to cell-specific oligonucleotide aptamer-based targeting ligands, to enhance the antigenicity of disseminated tumor lesions, promote immune memory, target immune modulation to the tumor lesion and enhance the uptake of tumor antigens by the professional antigen presenting system.

Current research interest

A multi-pronged approach to cancer immunotherapy using nucleic acid-based drug and drug delivery platforms

Immune therapy is emerging as a promising therapeutic modality for cancer patients underscored by the recent FDA approval of two immune acting drugs for melanoma and prostate cancer. Nonetheless, the therapeutic benefit of the drugs was modest, stressing the need to develop more potent and/or complementary treatments. Our cancer immunotherapy program is guided by three requisites that are paramount to the development of successful treatments for cancer. First and foremost, absent a “magic bullet” to treat cancer, we need to develop a combination approach of complementary and synergistic treatments. Second, need to pay attention to the feasibility of the therapy, from the standpoint of cost, complexity, and/or access to the drug. Third, arguably a main challenge in clinical oncology, need to address the dose-limiting toxicity of cancer drugs, including immune modulatory drugs.

Addressing feasibility, we are developing a new platform for drug and drug delivery consisting of short forms of nucleic acids, oligonucleotides (ODNs). Compared to antibody-based therapeutics, the short chemically synthesized ODNs are less expensive to develop and manufacture, conjugation chemistry is straightforward, and they are not likely to exhibit significant immunogenicity in the patient. The toxicity issue – the key aspect of our program – is addressed by targeting the ODN-based drugs, e.g. siRNAs, microRNAs, to the appropriate cells in vivo, the tumor and/or the immune cell. In vivo cell targeting in effect converts poorly-specific, and even nonspecific, drugs into a specific outcome. The targeting ligands used in our approach are oligonucleotide aptamers. Aptamers exhibit specificity and avidity that is comparable to and often exceeds that of antibodies, and can be generated against most, if not all, targets.

Metastasis is the main cause of death among cancer patients and the foremost challenge in cancer therapy. Using the aptamer-targeted RNA therapeutics platform, we are developing a combination of novel and unique, as well as clinically useful and broadly applicable, approaches with complementary and synergistic mode of action to enhance the immune susceptibility of the disseminated metastatic tumor lesions of the cancer patient. Targeting tumor cells we have developed a new paradigm in cancer immunotherapy (15) whereby new antigens, neoantigens, are expressed in tumor lesions, in effect making the tumor more “visible” to the immune system. Absence or reduced numbers of neoantigens in the patient’ tumor lesions was recently shown to be a major impediment to successful immune therapy. Given the ability to express new antigens in tumor cells in situ we are exploring ways to vaccinate against future tumors for patients in remission to prevent recurrence and for individuals at high risk of developing cancer whereby subjects are first vaccinated to induce immune responses against said neoantigens and if or when a tumor develops induce the same antigens in the tumor.

A complementary approach is to target immune modulation to tumors in order to reduce the toxicity of immune stimulatory drugs (17, 18), underscored by the experience of using Ipilumimab, a recently FDA-approved immune stimulatory antibody. The effectiveness of immune therapy is also dictated by the ability of the antitumor immune response to persist in the treated patient. To that end we are developing approaches to enhance the memory arm of the immune response by (aptamer) targeted (siRNA) inhibition of mTOR and other mediators in the vaccine-activated T cells (13, 19). A most recent approach we are developing is to enhance the uptake of tumor antigens by the professional antigen presenting system, the dendritic cells, by coating the tumor cells in situ with pre-existing polyclonal antibodies that are recruited to the tumor by aptamer targeted antigens/hapten specific to either vaccine-induced or naturally occurring antibodies.

Applications of aptamer-targeted nucleic acid therapeutics for immune manipulation, separately and/or in combination, have reached the cusp of clinical testing – a main challenge and current focus our program. The animal studies, having provided strong foundation for the feasibility and efficacy of this new platform, suggest that phase II indication-to-efficacy clinical trials, especially when using a judicious combination of two of the above strategies, could exhibit unprecedented therapeutic benefits in cancer patients.

Other Activities in the Department and University Wide Major Committees:

1. Teaching: Dendritic cell biology (Principle in Immunology, MIC 628); Tumor immunotherapy (Cancer Biology Program, CAB 612)

2. UM: SCCC IAB Scientific Advisory Committee; Translational track for PhD programs cmtee; K12 Mentored Translational Research Scholars Program Award cmtee; American Cancer Society (ACS) Institutional Research Grant Committee; CFAR Pilot awards committee; SCCC bridge grants committee

Research Profile
Pubmed Link