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Multiple Presentations on Telomerase at the AACR 2006 Annual


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Geron Corporation Announces Multiple Presentations on Telomerase at the AACR 2006 Annual Meeting

4/6/2006 7:30:00 AM EST


Geron Corporation (Nasdaq:GERN) announced presentations by collaborators and independent researchers at this year's AACR Annual Meeting, including a preclinical study of its telomerase inhibitor drug, GRN163L, from the laboratory of Dr. Jerry Shay at the University of Texas Southwestern Medical Center, Dallas, Texas, and a clinical study of its telomerase vaccine, GRNVAC1, in advanced prostate cancer patients from the laboratory and clinic of Dr. Johannes Vieweg at Duke University Medical Center, Durham, North Carolina. In addition, there were more than 100 other presentations on telomerase and telomeres, reflecting the growing body of evidence supporting the importance of telomerase in cancer biology and its potential as a universal cancer target for drug and vaccine development.

Anti-Cell Adhesive Effects of GRN163L in Cancer Cells

Previous studies from the Shay laboratory have shown that GRN163L reduces the tumorigenic potential of a human lung cancer cell line (A549-luc) both in vitro and in vivo (Cancer Research, 2005; 65(17):7866-73). Further studies reported here revealed that A549-luc cells were morphologically and functionally altered in vitro by GRN163L. Single doses of GRN163L prevented colony formation and significantly altered cell shape in tissue culture flasks. Cells treated with a mismatched control drug were unaffected. Scientists at Geron have seen similar effects of GRN163L on cells from other tumor types. The altered morphology occurred within 24 hours of treatment with GRN163L and was independent of telomerase inhibition or telomere length.

These morphological alterations were associated with a 50% reduction in cellular attachment in vitro and a 3-fold decrease in cell spreading surface area. In an in vivo model of lung cancer metastasis, in which tumor cells from an intravenous injection migrate to, attach and grow in lung tissue, a single dose of GRN163L at the time of animal inoculation with A549-luc tumor cells resulted in significant reduction in tumor burden at days 13, 20 and 27 of tumor progression.

These data suggest that the observed effect of GRN163L on lung cancer cells may be mediated in part by the altered cell adhesion induced by this novel cancer therapeutic agent, and that GRN163L may have additional benefit in prevention of metastasis.

In Situ Activation of Dendritic Cells with Imiquimod for Cancer Immunotherapy

Prior studies have demonstrated the induction of CD8+ anti-telomerase T-cells in patients with prostate cancer using weekly intradermal injections of autologous, ex vivo activated, telomerase RNA-loaded dendritic cells (DCs). These telomerase-specific cellular immune responses were unaccompanied by significant toxicity and were associated with clearance of circulating prostate cancer cells and significant prolongation of PSA doubling times (Journal of Immunology, 2005; 174: 3798-3807). The current study was undertaken to define the immune response in advanced metastatic prostate cancer patients resulting from the weekly intradermal injection of telomerase RNA-loaded autologous DCs activated in vivo. In vivo activation was achieved by injecting immature DCs into dermal sites conditioned by the topical application of low, intermediate or high doses of the immunomodulator Imiquimod cream, applied 1-5 days before each injection.

Biopsies of Imiquimod-treated skin were analyzed for secretion of cytokines. Imiquimod application led to increases in levels of the cytokines RANTES and MCP-1, but not other cytokines known to facilitate DC maturation such as TNFalpha, MIP-1alpha, IL-1beta, IL-6, IFN-alpha, and PGE-2. Six weekly injections of telomerase RNA-loaded, immature autologous DCs resulted in robust hTERT-specific T-cell responses in the intermediate Imiquimod dose group only (.25mg applied at days -3 and -1 prior to weekly DC injections) with only modest responses in the low and high dose Imiquimod groups.

As seen in the prior Phase 1-2 study with patients receiving ex vivo matured DCs, telomerase-specific T-cell responses observed in this study were again associated with prolongation of PSA doubling times. These results suggest that optimized topical application of Imiquimod cream prior to vaccination with immature hTERT RNA-loaded autologous DCs may achieve hTERT-specific immune responses comparable to those achieved with hTERT RNA-loaded autologous DCs fully matured ex vivo, including the positive impact on patient PSA doubling times.

Telomerase Inhibition (GRN163L)

Telomerase Gene Rescue Promotes Hepatocarcinogenesis

Dr. Leonard Rudolph and colleagues at the Medical School Hannover in Germany demonstrated the importance of telomerase activity in a mouse model of hepatocellular carcinoma (HCC). In this model, designed to mimic human carcinogenesis, telomere shortening, genetic instability, and chronic liver damage were engineered into telomerase positive and negative mouse strains. Appearance of pre-neoplastic foci was observed in both telomerase negative and telomerase positive mouse strains, indicating that pre-malignant lesions can form without telomerase. However, the frequency of malignant HCC was dramatically increased in the telomerase positive mice compared to the telomerase negative mice, suggesting that telomerase is essential for cancer progression. These data support the critical role of telomerase in cancer progression and reinforce the rationale for the ongoing clinical studies of GRN163L in solid tumor and hematologic cancers.

In other presentations at the meeting, evidence was presented for relatively rapid, non-telomere-dependent effects of telomerase in cancer cells, such as resistance to apoptosis. In one study, presented by scientists at the Institute Gustave Roussy, Villejuif, France, it was shown that down-regulation of hTERT, the catalytic component of telomerase, sensitizes tumor cells to DNA damaging agents, potentially through a role of hTERT in mitochondrial function. Such studies provide insight into how telomerase inhibition might be used in combination with chemotherapies.

Telomerase Vaccine (GRNVAC1)

Immunologic and Clinical Outcomes Following Telomerase Peptide Vaccination in Patients with Metastatic Breast Cancer

Dr. Robert Vonderheide and colleagues at the University of Pennsylvania School of Medicine in Philadelphia, Pennsylvania studied telomerase vaccination in 17 patients with metastatic breast cancer using a telomerase peptide administered subcutaneously with an adjuvant and GM-CSF. Eleven of seventeen patients responded immunologically with hTERT-specific CD8+ T-cells. Three patients who underwent repeated tumor biopsies had hTERT-specific CD8+ tumor infiltrating lymphocytes (TILs) in their tumors after, but not before, vaccination. In two of these subjects, TILs were associated with tumor necrosis. Clinical impact of vaccination was suggested by survival analysis which showed a median survival among the six non-responders of 12.6 months, whereas the median survival of the immunological responders had not been reached at a median follow up of 15.7 months (range 0.9 to 22.3 months). Two responder patients remain progression free after 15 and 22 vaccinations (14 and 21 months, respectively). Dr. Vonderheide reported that none of the patients in the long-term studies showed signs of toxicity in normal tissues due to vaccinations. These data suggest that hTERT vaccination may hold promise as an immunotherapy for metastatic breast cancer.

Presentations Indicate the Potential for Geron Therapies

"We are pleased to see continued demonstration of the critical role of telomerase in human cancer as evidenced by the many presentations on telomerase at this year's AACR Annual Meeting," said Calvin Harley, Ph.D., Geron's chief scientific officer. "Geron's two cancer therapeutic products target telomerase in unique and specific ways. We look forward to the generation of additional clinical data supporting the utility of both our drug and vaccine over the coming months."

Geron is a biopharmaceutical company focused on developing and commercializing three groups of products: i) therapeutic products for oncology that target telomerase; ii) pharmaceuticals that activate telomerase in tissues impacted by senescence, injury or degenerative disease; and iii) cell-based therapies derived from its human embryonic stem cell platform for applications in multiple chronic diseases.

This news release may contain forward-looking statements made pursuant to the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. Investors are cautioned that such forward-looking statements in this press release regarding potential applications of Geron's telomerase technology and future clinical trial results constitute forward-looking statements that involve risks and uncertainties, including, without limitation, risks inherent in the development and commercialization of potential products, uncertainty of clinical trial results or regulatory approvals or clearances, need for future capital, dependence upon collaborators and maintenance of our intellectual property rights. Actual results may differ materially from the results anticipated in these forward-looking statements. Additional information on potential factors that could affect our results and other risks and uncertainties are detailed from time to time in Geron's periodic reports, including the annual report on Form 10-K for the year ended December 31, 2005.

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The telomerase focus is going to be very interesting to follow (something I have been interested in as well) within the scientific community. It's certainly a mysterious little ribonucleoprotein that appears key in the survivability of the cells. How they are going to isolate a vaccine that only targets cancer cells will be worth watching: telomerase is also readily prevelent in fast-reproducing cells such as blood, hair, skin, etc.

Would be nice if they could encourage perhaps telomerase presence in healthy cells/immune system to permit the body to actually be really good at fighting off cancer or carcinogenic agents in the first place. Doesn't look like current research into cell behavior would permit that though -- "normal" cells apparently handle telomerase differently and become genetically unstable from what I've found so far when they have tried that. (rats!!!)


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