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Held Immediately following the Targeted Cancer Therapies Conference

Day 2

September 20

7:15 Registration, Poster Set-Up & Morning Coffee

7:55 Chairperson's Opening Remarks
Dr. Daniel Chelsky, CSO, R&D, Caprion Pharmaceuticals

8:00 Immune Monitoring Dr. Rafick-Pierre Sékaly, Professor, Laboratory of Immunology, Unversity de Montreal; Scientific Director, CANVAC

Radiopharmaceuticals

8:40 Update on Radio-Immunotherapy
Dr.Roger Macklis, Prof and Chair, Radiation Oncology, Cleveland Clinic
Radio-Immunotherapy is currently being investigated as a means of eradicating designated populations of cancer cells using a combination of antigen-specific antibody therapy turbocharged through the chemical attachment of beta particle emitting radioactive atoms. Two of these biologically targeted agents have now received FDA clearance, both for CD20+ B cell NHL. Clinical results with each of these compounds (Y-90 Ibritumomab tiuxetan (Zevalin) and I-131 Tositumomab) produce overall response rates on the order of 70% with complete response rates of approximately 30%. Toxicity for these biologically targeted radiopharmaceuticals appears to be MUCH less than comparable chemotherapy regimens. However, mechanisms of action are not entirely clear and the optimal use of these compounds is currently being investigated. The Cleveland Clinic has an active multidisciplinary research and clinical program in this area. This talk will briefly review the background and clinical results achieved to date and discuss the next set of clinical patient groups appropriate for this growing field of targeted therapeutics.

9:05 Antibody Based Therapy of Prostate Cancer Targeting a Novel Prostate Antigen
Dr. Renate Parry, Senior Scientist, Cancer Research, Berlex Pharmaceuticals
The talk will summarize pre-clinical development of a human monoclonal antibody that has the potential of becoming a specific radio-pharmaceutical for prostate cancer and metastasis. The story comprises discovery of the target using genomics technologies, its validation, producing and characterizing human mAbs as well as efficacy studies, including dose-response curves, in xenograft models of prostate cancer. Preliminary data will be presented indicating the versatility of the antibody as a PET imaging reagent.

9:30 Combination of Radiation Therapy and Immunoprophylaxis for Advanced Gliomas in Rats
Dr. Henry M. Smilowitz, Department of Pharmacology, University of Connecticut Health Center
Our laboratory has been studying the combination of radiation therapy and immunoprophylaxis for advanced intracerebral gliomas in rats. Using the 9L gliosarcoma model for moderately aggressive gliomas, we have studied the combination of LINAC radiosurgery, boron neutron-capture therapy and microbeam radiation therapy with autologous cell vaccination (IMPR) and GMCSF-transfected autologous cell vaccination (GMIMPR). We have shown that the combination of BNCT and IMPR is effective but the combination of LINAC or MRT and IMPR is ineffective. The combination of LINAC or MRT and GMIMPR is highly effective. We hypothesize that the more effective GMIMPR is required by radiation methods that kill fewer cells. Our data raises the hypothesis that the rats that benefit the most from immunotherapy are the rats that benefit the most from radiation therapy. In collaboration with Jean A. Laissue2, Jeffrey A. Coderre3, and Daniel N. Slatkin4; 2 Institut fur Pathologie der universitat, Bern; 3Department of Nuclear Medicine, MIT; 4Brookhaven National Laboratory.

10:20-11:00  Coffee Break, Poster and Exhibit Viewing

Antibodies

11:25 Selection of Functional Antibodies
Dr. Jörg Hoheisel, Head, Department of Functional Genome Analysis, Deutsches Krebsforschungszentrum
There is a growing need for antibodies to be used in early, preventive cancer diagnostics and tumor specific therapeutics. Antibody phage display libraries have become an important source for rapid isolation of novel antibodies. In general, however, selection of specific antibodies from phage display libraries requires laborious subtraction protocols and ­ in spite of elaborate pre-incubations and other processes ­ is limited by high background binding of non-specific phage and relatively low binding of specific phage. Also, good binders frequently get lost during the process. We established a process that circumvents the above mentioned problems and offers an opportunity selectively to identify highly specific and affine antibodies. The process was applied to the analysis of samples from 
pancreatic cancer.

11:50 Suppressing Tumor Growth 
Dr. Bruce Freimark, Director of Molecular and Protein Biology, CancerVax Corp.

12:15 Discovery and Validation of a Promising New Target for Therapeutic Monoclonal Antibodies: A Transmembrane Protease Overexpressed in Human Ovarian and Pancreatic Cancers
Dr. Jackie Papkoff, VP Discovery and Therapeutics, diaDexus, Inc.
Through genomics efforts we identified an mRNA encoding a transmembrane protease (DD-O115) that is overexpressed in human ovarian and pancreatic cancer with low or no expression in normal tissues. Immunohistochemical studies with antibodies against DD-O115 revealed strong tumor cell surface staining in sections of human cancers. Whereas siRNA-mediated knockdown of DD-O115 expression in cultured tumor cells led to increased apoptosis, overexpression of DD-O115, but not a DD-O115 mutant lacking protease activity, induced growth of test cells in soft agar and tumor growth in SCID mice. We generated monoclonal antibodies which are able to bind live tumor cell lines and inhibit the enzymatic activity of DD-O115. The tumor-specific over-expression of DD-O115 and its functional role in promoting malignant transformation make this cell surface antigen an ideal target for a monoclonal antibody therapeutic strategy; mouse xenograft imaging and efficacy studies are in progress.

1:10 Lunch On Your Own

2:25 Chairperson's Remarks
Dr. Sandra Gaston, Principal Investigator/Laboratory Director, Department of Surgery, Beth Israel Deaconess Medical Center

Using Phage Display

2:30 Identification of Novel Cancer Targets and Therapeutics Using Phage Display
Dr. Neil Goldstein, President, Antyra Inc.
We utilize high diversity phage display libraries to isolate pharmacologically active peptides (called HotSpot Pharmacophores or HSPs) which can both identify novel targets and be used as therapeutics in their own right. Using this approach, we have identified several HSPs, which can block proliferation of cancer cells in vitro and in vivo. We are presently moving one candidate into the development stage towards clinical trials.

2:55 Generation of Human T-Cell Receptors with Picomolar Affinity for Targeting Cancer Cells
Dr. Yi Li, Head of Phage Display, Avidex ltd
Peptides derived from almost all proteins, including disease-associated proteins, can be presented on the cell surface as peptide­human leukocyte antigen (pHLA) complexes. T cells specifically recognize pHLA with their clonally rearranged T-cell receptors (TCRs), whose natural affinities are limited to 1­100 microM. We report the directed evolution of high-affinity TCRs specific for the NYESO- 1157­165 tumor-associated peptide antigen­HLA-A*0201 complex, with affinities of up to 26 pM, and we demonstrate their high specificity and sensitivity for targeting of cell-surface pHLAs.

Technological Progress

3:20 Comprehensive Proteomics Approach for Immunotherapy Target Identification in Cancer 
Dr. Daniel Chelsky, CSO, R&D, Caprion Pharmaceuticals
Global changes that accompany the conversion of healthy epithelial cells into tumors can now be tracked with mass spectroscopy-based proteomics. Plasma membranes were isolated from tumor cells and matching normal epithelium and compared to identify those proteins up-regulated in the tumor. Tumor and normal tissue from thirty lung cancer patients was obtained and compared at the level of protein digests to identify approximately 300 membrane proteins as potential antibody therapy targets. Included among the identified proteins are most of the known immunotherapy targets discovered to date as well as many not previously seen to be up-regulated in cancer. This comprehensive approach to comparing related samples, along with the ability to successfully determine protein identity on a large scale, is proving to be a very powerful tool and will supplant the need to query individual proteins at the discovery phase of research. The results of the lung study and a similar study in colon cancer will be presented along with the methods used to obtain the results.

3:45 Gene Expression Profiling with an High-Throughput Integrated Approach
Dr. Marie-Claude Gingras, Assistant Professor, Pediatrics/Cancer Center, Baylor College of Medicine
We have developed a novel approach to facilitate gene expression profiling that combines the selective and normalization power of suppression subtractive hybridization, the high-throughput sequencing ability of concatenated cDNA sequencing, and the quantitative analytical power of reverse transcriptase real-time quantitative PCR. The advantage of this approach is not only associated with the automation of the cloning and sequencing process, and the computerization of the BLAST analysis, but also relies on the direct identification of every differentially expressed gene and the identification of rare transcripts not present on the most recent commercially available microarray. Using this technique, we have identified several low-risk markers in Acute Lymphoblastic Leukemia.

4:10 Coffee Break, Poster and Exhibit Viewing

4:50 Optimization of Antibody-Enzyme Conjugates for the Tumor Targeted Release of Melphalan
Dr. Enrique Escandon, Genencor Intl., Inc.
We developed fusion proteins between beta-lactamase and antibody fragments that bind with high affinity and selectivity to tumor tissues. The fusion proteins were optimized for stability, expression, and low immunogenicity. Binding of these proteins to tumor tissue leads to the tumor-targeted activation of lactam-based prodrugs and the tumor-selective release of melphalan. We observed good in vivo efficacy after a single round of treatment.

5:15 Mapping Molecular Targets in Human Tissue Biopsies and Surgical Specimens: Tissue Print Micropeel Technologies
Dr. Sandra Gaston, Principal Investigator/Laboratory Director, Department of Surgery, Beth Israel Deaconess Medical Center
Recent advances in molecular technologies have led to acceleration in the identification of potential biomarkers for human cancers. To realize the full potential of this wealth of new biomarkers in the development of targeted therapies for solid tumors, it is essential that we develop new strategies for profiling human tissue specimens that are compatible with the demands and restrictions of the clinical setting. My laboratory has developed a set of novel tissue print micropeel techniques that allow us to map a series of molecular marker profiles from an extended area of a human tissue sample without damaging the specimen (Gaston et al. Tissue-Print and Print-Phoresis as Platform Technologies for the Molecular Analysis of Human Surgical Specimens: Mapping Tumor Invasion of the Prostate Capsule. Nat Med. 2005;11(1):95-101). Because our tissue print platform supports both proteomic analysis and PCR-based DNA and mRNA profiling techniques, it can be used to generate detailed molecular cross-sections that can be layered directly over corresponding histological and radiological images. Such extensively annotated maps of human tissue and tumor specimens can be used for target-based tumor classification and for monitoring molecular responses to target-based therapies. I present an overview of our tissue print micropeel technologies, with specific examples of the application of these technologies in the molecular assessment of human tissue biopsy and surgical specimens.

5:40 Targeting the Ubiquitin Pathway: An Emerging Anticancer Approach
Dr. Michael Mattern, Vice President, Research, Progenra, Inc.
Targeted anticancer therapy can be directed toward facilitating cellular activity of tumor suppressors or, alternatively, inhibiting the activity of tumor promoting oncoproteins. The ubiquitin proteasomal pathway, which regulates the cellular lifetime of most proteins, consists of enzymes that can do both ­ ubiquitin E3 ligases, which tag proteins for degradation, and ubiquitin isopeptidases, which can remove ubiquitin tags, sparing proteins from degradation. Inhibitors or activators of these enzymes have the potential to prolong the cellular lifetime of tumor suppressors and to eliminate oncoproteins. We have developed novel assays for both E3 ligase activity and isopeptidase activity. Screening approaches to discover effectors of E3 ligases and isopeptidases for development as anticancer drugs will be described in detail.

6:05 End of Day Two