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Professor Zelig Eshhar
E-mail: zelig.eshhar@weizmann.ac.il
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Research Interests: (updated June, 2009)
Redirecting the Specificity of Effector Lymphocytes to Cancer and Regulatory T Cells to Inflammatory Diseases
To expand the recognition spectrum of T cells and redirect them to predefined targets, we endowed effector T and NK cells or regulatory T cells (Tregs) with antibody-type specificity using chimeric receptor genes. Several configurations employing the antibody V region cDNA in the form of scFv or ligands to target cell receptors linked to triggering subunits of the FcR or CD3 complex were constructed. Followed to the expression of these constructs in T cells, we have demonstrated their ability to trigger an MHC non-restricted or dependent T-cell upon interaction with their specific targets. In order to mediate co-stimulatory signal the cytoplasmic domains of CD28 and/or CD137 (4-1BB) were added in tandem to tripartite chimeric receptors (TPCR) and have been proven to provide a full activation and avoid activation induced cell death (AICD) of TPCR-transduced T cells independently of the presence of co-stimulatory ligands.
- The antitumor activity of human and mouse effector cells expressing the TPCR (nick-named T-Bodies) recognizing various tumor associated antigens (TAA) such as erbB2, MUC-1, CEA, CD24 on prostate, breast and pancreatic adenocarcinomas have been tested in murine models in which human tumor xenografts have been orthotopically transplanted to either immunodeficient mice, or in transgenic strains of mice that develop organ-specific tumors over-expressing the human TAA. Adoptively transferred T-bodies could specifically reject established tumors and completely cure a high proportion of the tumor-bearing mice. A pre-requisite of an effective treatment required the pre-conditioning of the mice by lympho-depleting protocols, such as cyclophosphamide or sub-lethal irradiation. In certain cases, the engineered T cells were proven effective to slow the growth and even reject bone and lung metastases in experimental models.
- Antigen-specific Tregs are extremely rare in our body. We have hypothesized that endowing Tregs with specificity to the inflamed organ by the T-body approach could provide an efficient and feasible therapeutic mean to autoimmune inflammatory disease TNBS. In this model of inflammatory bowel disease (IBD) the redirected Tregs proved to be 10 fold more effective in the suppression of the experimental disease. Most of the control or untreated mice succumb to the acute colitis, while relatively very small of TNP-specific Tregs were sufficient to prevent the disease and rescue the treated mice. Moreover, we have demonstrated the �bystander effect� in which the engineered Tregs can be redirected to an antigen that is not necessarily related to the pathogen that cause the disease but an innocent antigen present on the inflamed organ. Apparently, the TPCR directs the Tregs to home to and accumulate at the inflamed site and upon its binding to its target antigen it activates the Tregs to secrete their anti-inflammatory cytokines.
Predicting the Outcome and Response to Therapy in Prostate Cancer (together with Prof Eytan Domany)
- One of the major research activities in Eshhar�s laboratory focused on the establishment of prostate tumor grafts to allow various studies using relatively fresh tumors of patients in immune-compromised animals (SCID mice). Such an experimental model has been used to study the therapeutic effects of genetically engineered T-bodies, as described above. In another study, these xenografts have been used to search for genes that differ in their expression level between radio-resistant and sensitive phenotypes of human prostate cancer. Prostate cancer (PC) xenografts and cell line were tested for their sensitivity to irradiation and could be distributed into tow groups - irradiation resistant and irradiation sensitive phenotypes. Analysis of the transcription profiles of these genes revealed some 110 genes whose profile of expression differed between the human PC xenografts that were classified as radio-resistant and those that were radio-sensitive. To further validate this data set, PC specimen from patients with known outcome are required. It is hoped that with further validation the outcome of this research will be useful to predict at early diagnosis whether a patients with a primary PC will be benefited from irradiation that is one of the two major mainstay in PC treatment.
- In another study, Eshhar's group has characterized (with Prof A. Harmelin) two strains of the TRAMP transgenic mouse that develops a PC at puberty (TRAMP), and that differ in the type and aggressiveness of the tumor they develop. In a search for genetic correlates to the human disease whose PC manifests different patterns of progression, analysis of genes whose expression profile is associated with the aggressive phenotype of the TRAMP was performed. In the search for genetic-background signature for outcome, a promoter analysis of the gene array data was carried out. One of the clusters that has been found is enriched with immune response related genes, and shows higher expression levels in the normal samples of the less aggressive TRAMP strain compared to the more aggressive strain. An interesting analysis is on its way that compares the mouse data to that available for human prostate and other cancers.
In addition to his other research, Prof Eshhar is also a partner investigator for the Health Program of �ATTACK� project for the specific treatment of cancer of The European Commission Quality of Life 7th Program.
Nitzan Adam, M.Sc. student
Dan Blat, Ph.D. student
Liat Elboim, M.Sc. student
Eran Elinav, M.D., Ph.D. student
Anat Globerson, Ph.D. student
Itai Kela, Post doctoral Fellow
Amit Maliar, M.D., Ph.D. student
Assaf Marcus, Ph.D. student
Charlotte Servais-Mavor Ph.D., Post doctoral Fellow
Shay Yaari, M.Sc. student
Tova Waks, Lab Assistant