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Biotech / Medical : Cistron Biotechnology(CIST)$.30 -- Ignore unavailable to you. Want to Upgrade?

To: Rudy Saucillo who wrote (1119)	4/27/1998 7:35:00 PM
From: scaram(o)uche	Read Replies (1) \| Respond to of 2742

>> I spoke with Hal Smith, CIST's PR person, this morning. He stated that Cistron is now actively involved in cancer vaccine research, and that this work involves "an outside party." This is good news and is a natural follow-on to the reacquisition of the GTI (Sandoz/Novartis) sub-license for this research. Hopefully, news of a collaboration will be forthcoming. Interestingly, today's (4/27) BioCentury has a lead article on cancer vaccine research. A number of companies/approaches are discussed. Clearly some of these approaches - as you've outlined previously - are relevant to CIST. This is a great 'primer.' I recommend that anyone interested go to the BioCentury website biocentury.com and request a copy. Hal also mentioned that CIST's flu vaccine work with Novavax and their wound healing work are proceeding. Also, Galton and BlueStone are working closely and are in active discussions with a number of companies. << Thanks, Rudy. All good news. However, it all could have been done 16 months ago, when the rationale was set, engraved(), under Brucie's nose. Would you prefer to see "collaborations" or would you rather see IL-1 bundled with the cash and sold out from under his "management"? Hal has been polite and professional. engraved...... Dear Brucie: Here's a good business plan. Love and smooches, Ricky

To: Rudy Saucillo who wrote (1119)	4/29/1998 1:33:00 PM
From: Rudy Saucillo	Read Replies (2) \| Respond to of 2742

A couple of notes... (1) I spoke with Hal Smith again this morning. We had a miscommunication about the status of CIST's cancer vaccine research. Yes, they have reacquired the GTI sublicense as noted in the last quarterly report. No, they are not actively involved in new research with another company. I would be surprised if they're not pursuing this, however, since that's the only reason to reacquire the (long dormant) sublicense. (2) I found a description (below) of current IL-1b research being performed at Wash. U. Interesting stuff...researchers are investigating the therapeutic potential of IL-1. Rudy PHYSIOLOGIC AND THERAPEUTIC ROLES OF TUMOR NECROSIS FACTOR AND INTERLEUKIN-1 Robert D. Schreiber, Ph.D. Keywords: immunology, cytokines, TNF, IL-1, cell biology Tumor Necrosis Factor (TNF) and Interleukin-1 (IL-1) are pleiotropic cytokines that play important roles in promoting inflammatory reactions. We have initiated two research projects aimed at defining the physiologic roles of TNF and IL-1 in vivo and evaluating the therapeutic potential of these agents in the treatment of immunopathological diseases. Our recent work has demonstrated that TNF or IL-1 can completely and reversibly suppress immune responses if the agents are supplied to an individual prior to an immunologic challenge. Working in murine model systems we have blocked xenograft islet rejection and inhibited T cell priming to protein antigens by daily administration of TNF or IL-1. Our goal in this first project is to define the molecular mechanisms that underlie the immunosuppressive effects of these agents and explore whether the actions of these cytokines can be exploited to generate novel immunosuppressive therapeutics. The second project focuses on developing novel approaches to define the functional roles of TNF and IL-1 in vivo. Our laboratory has been one of the leaders in using neutralizing cytokine-specific monoclonal antibodies to elucidate the physiologic roles of endogenously produced cytokines in animal models. While these approaches have helped to document the general in vivo importance of TNF and IL-1, they have not defined the individual functional responses induced by these proteins in specific cellular targets in vivo. Recently, we ablated cellular responsiveness to particular cytokines in vitro by introducing functionally inactive cytokine receptors into homologous cells. The inactive receptors act as a dominant negative mutation and thereby completely paralyze the ability of the cell to respond to its cytokine agonist. We wish to capitalize on this observation and explore whether we can generate mice with tissue-specific defects in responsiveness to TNF and IL-1 by expressing inactive TNF- or IL-1-receptor mutants behind tissue-specific promoters. This approach will allow us to define the actions of each cytokine directly on specific tissues in an environment in which responses of other tissues to TNF and/or IL-1 are unaltered. These experiments should provide new insights into the biology of TNF and IL-1 and may result in the development of novel therapeutic approaches to regulate immune and inflammatory responses.

To: Rudy Saucillo who wrote (1119)	5/1/1998 1:26:00 PM
From: Rudy Saucillo	Read Replies (1) \| Respond to of 2742

Here's an update to the Vical/R.Levy lymphoma vaccine development activity (excerpted from VICL's 10K dated 3/30/98). I've also included the Levy abstract (posted previously on this thread) that describes the use of IL-1b in this type of cancer vaccine. I have no info on CIST partnership discussions, but it's clear that the VICL/Levy work and the CNTO license should be of interest. Rudy "In collaboration with Dr. Ronald Levy of Stanford University Medical Center, the Company is developing a naked DNA anti-idiotype vaccine, VAXID, against low-grade non-Hodgkin's B-cell lymphoma. This type of lymphoma is characterized by a slow growth rate and excellent initial response to chemotherapy or radiotherapy; however, a regular pattern of relapse to a diffuse aggressive lymphoma occurs for which no curative therapy has been identified. Clinical studies involving administration of either monoclonal anti-idiotype antibodies or patient-specific B-cell lymphoma idiotype protein have resulted in prolonged remissions; however, these therapies are limited by the time and effort required to produce the drug product. VAXID is a DNA plasmid that encodes the patient-specific idiotype of the B-cell tumor immunoglobulin. In preclinical studies, Dr. Levy showed that the injection into mice of a murine B-cell lymphoma idiotype plasmid resulted in strong anti-idiotype immune responses and significant protection against tumor challenge. Based on these preclinical studies and additional studies conducted at Vical, the Company believes that immunization of post-chemotherapy patients with VAXID could result in the elimination of residual disease and the prevention of the relapse of disease. In October 1997, a Phase I/II clinical trial of VAXID began at the Stanford University Medical Center under the direction of Dr. Levy. In February 1998, Vical entered into a license agreement allowing Centocor, Inc. to use Vical's naked DNA technology to develop and market certain gene-based vaccines for the potential treatment of certain types of cancer." ---- J Immunol 1996 Dec 15;157(12):5503-5511 A nine-amino acid peptide from IL-1beta augments antitumor immune responses induced by protein and DNA vaccines. Hakim I, Levy S, Levy R Division of Oncology, Department of Medicine, Stanford University Medical Center, CA 94305, USA. The idiotypic determinants of B cell lymphoma provide a tumor-specific Ag and a target for immunotherapy. We have developed several generations of idiotype vaccines that were tested in an animal model, the 38C13 mouse B cell lymphoma. Initially we showed that effective tumor immunity was elicited by the syngeneic Id when it was conjugated to a carrier protein and mixed with an adjuvant. A subsequent generation of Id vaccines eliminated the need for a carrier protein and for an adjuvant by incorporating cytokines into fusion proteins containing the Id. A third generation of vaccines consisting of naked DNA encoding the Id-granulocyte-macrophage colony-stimulating factor (GM-CSF) fusion proteins was equally effective in inducing tumor immunity. To determine whether Ig variable regions, in the absence of constant regions, could be immunotherapeutic in this model, we tested the use of single-chain Fv (scFv). scFv proteins, produced in bacteria, and naked DNA encoding scFv were used in this study. scFv was tested alone or fused to GM-CSF or an immunoenhancing peptide derived from IL-1beta. Here we demonstrate that scFv-GM-CSF was effective only when injected as a protein, not as a DNA vaccine. In contrast, both scFv-IL-1beta peptide fusion protein and naked DNA encoding it induced tumor immunity that protected mice from tumor challenge.