Polynucleotides for Inhibiting Metastasis and Tumor Cell Growth

BioCrystal, Ltd.  (Assignee)
U.S.  Patent Number 6,268,350
Filed:  January 7, 2000
Date of Patent:  July 31, 2001

Preface.  It has been demonstrated that Fas Ligand (FasL) expression causes a more aggressive phenotype in tumor cells.  It has been proposed that the increase in malignancy is due to induction of T cell apoptosis by tumor cell-derived FasL.  BioCrystal demonstrated experimentally that the administration of FasL antisense and FasL sense polynucleotides into and around a solid FasL negative tumor effectively produced a reduction in the tumor growth rate and suppression of invasion and metastasis compared with controls. 

Background.  (Invention Summary) BioCrystal’s novel discoveries that metastatic cells and nonadherent tumor cells which are Fas-expressing (“Fas+”) can be induced to apoptosis by contact with FasL+ tumor cells; and that inducing FasL expression on FasL(-) tumor cells does not confer immune privilege to these cells in vivo, but instead targets the tumor cells for destruction.  Additionally, as disclosed by the present inventor (see, e.g., Barbera-Guillem et al., 2000, Cancer Immunol.  Immunother.  48: 541-549) B lymphocytes exposed to shed tumor antigen can promote tumor progression.  FasL+ tumors can contact and induce cytotoxicity of these Fas+ tumor-promoting B cells.  Also disclosed herein is the discovery that by introducing a therapeutically effective amount of a composition comprising polynucleotide incorporating FasL anti-sense in an area local or regional to a tumor, tumor growth and/or metastasis is inhibited.  Additionally, disclosed herein is the discovery that administration of a therapeutically effective amount of a composition comprising one or more polynucleotides in an area local or regional to a tumor can effect an inhibition of tumor growth and/or metastasis.  Such a composition comprises a combination of one or more polynucleotides comprising antisense to FasL, and one or more sense polynucleotides encoding FasL. 

This procedure is proposed for use in the treatment of cancer patients with a primary tumor comprised of a solid, non-lymphoid tumor and/or its metastasis, or to individuals who have been treated for a solid, nonlymphoid tumor and thereby inherently carry the risk of recurrence because of recirculating tumor cells.  In either case such individuals are at risk for developing, or have developed, a pro-tumor immune response.  Such treatment has been shown experimentally to effect the Fas-mediated destruction of both the tumor and tumor-promoting B cells in the vicinity of the tumor.  This treatment has been the subject of publication (Gene Therapy, 2001, 8:209-214).  Sense and antisense therapies may be applied in a site-directed manner, rather than systemically. 
 

Contact Information for Licensing or Sale:    Jeffrey R. Bergen
                                                                      CEO
                                                                      BioCrystal, Ltd. 
                                                                      575 McCorkle Boulevard
                                                                      Westerville, OH 43082
                                                                      Phone: 614-818-1170 ext 208
                                                                      Email: jbergen@biocrystal.com
                                                                      Mobile: 614-940-7781