Interleukin-3 gene therapy for cancer

Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus

Reexamination Certificate

Rate now

  [ 0.00 ] – not rated yet Voters 0   Comments 0

Details

C514S04400A, C536S023500, C536S023100, C435S320100, C435S325000, C435S455000

Reexamination Certificate

active

06495131

ABSTRACT:

The present invention lies in the field of anti-cancer (gene) therapy. In particular, the invention relates to selective killing of (solid) tumor cells in a mammal by gene delivery via the blood circulation.
Many different kinds of solid tumors occur in the body of mammals, including humans. In many cases these tumors are extremely difficult to treat, especially in advanced cancer with metastases. Currently available therapies include surgery, radiation therapy, chemotherapy, radio-immunotherapy, cytokine treatment and hyperthermia. All these therapies have important limitations and disadvantages. E.g., surgery can only be performed on localized, accessible tumors; radiation and chemotherapy are associated with both acute and latent toxicity, and responses are often limited; radio-immunotherapy and hyperthermia have limited application and effectivity; and cytokine administration is often associated with toxicity and evokes many pleiotropic side-effects. Often said therapies are combined to improve efficacy and to decrease toxic side-effects. However, in general, the effectivity of said therapies and their combinations is still unsatisfactory.
More recently, gene therapy has been proposed as a novel approach to treat malignancies. The concept of gene therapy comprises the introduction of a molecule carrying genetic information into cells of a host, whereby said genetic information has a functional format. Said genetic information may comprise a nucleic acid molecule that encodes a protein. In this case said functional format means that the protein can be expressed by the machinery of the host cell. The genetic information may also comprise or encode nucleic acid molecules with a sequence that is complementary to that of a nucleic acid molecule present in the host cell. The functional format in this case is that the introduced nucleic acid molecule or copies made thereof in situ are capable of base pairing with the complementary nucleic acid molecule present in the host cell. Said genetic information may furthermore comprise a nucleic acid molecule that encodes or is itself a so-called ribozyme or deoxyribozyme. In this case said functional format means that said nucleic acid molecule or copies made thereof in situ are capable of specifically cleaving a nucleic acid molecule present in the host cell. Said genetic information may furthermore comprise a nucleic acid molecule that encodes or is itself a so-called decoy molecule. In this case said functional format means that said nucleic acid molecule or copies made thereof in situ (nucleic acid molecules or proteins) are capable of specifically binding a peptide molecule present in the host cell.
Said introduction of a molecule carrying genetic information into cells of a host is achieved by various methods known in the art. Said methods include, but are not limited to, direct injection of naked DNA constructs, bombardment with gold particles loaded with said constructs, and macromolecule mediated gene transfer using, e.g., liposomes, biopolymers, and the like. Preferred methods use gene delivery vehicles derived from viruses, including but not limited to adenoviruses, retroviruses, vaccinia viruses and adeno associated viruses. Because of the much higher efficiency as compared to e.g. vectors derived from retroviruses, vectors derived from adenoviruses (so-called adenoviral vectors) are the preferred gene delivery vehicles for transferring nucleic acid molecules into host cells in vivo.
The adenovirus genome is a linear double-stranded DNA molecule of approximately 36000 base pairs. The adenovirus DNA contains identical Inverted Terminal Repeats (ITR) of approximately 100 base pairs with the exact length depending on the serotype. The viral origins of replication are within the ITRs exactly at the genome ends. Adenoviruses can be rendered replication defective by deletion of the early-region 1 (E1) of their genome. Vectors derived from human adenoviruses (so-called adenoviral vectors), in which at least the E1 region has been deleted and replaced by a gene-of-interest, have been used extensively for gene therapy experiments in both pre-clinical and clinical phase. Apart from replication defective adenoviral vectors, helper independent or replication competent vectors, either or not containing a gene-of-interest, can also be used for gene therapy purposes. Adenoviral vectors have a number of features that make them particularly useful for gene therapy for malignancies. These features include (1) the biology of adenoviruses is characterized in detail, (2) adenoviruses are not associated with severe human pathology, (3) adenoviruses are extremely efficient in introducing their DNA into host cells, (4) adenoviruses can infect a wide variety of cells and have a broad host-range, (5) adenoviral vectors allow insertion of relatively large fragments of foreign DNA, (6) adenoviruses can be produced in large quantities with relative ease, and (7) adenoviral vectors are capable of transferring nucleic acid molecules very efficiently into host cells in vivo (Brody and Crystal, Ann. N. Y. Acad. Sci. 716(1994):90-101).
The present inventors and their coworkers as well as others have demonstrated that recombinant adenoviral vectors efficiently transfer nucleic acid molecules to the liver of rats (Herz and Gerard, Proc. Natl. Acad. Sci. U.S.A., 96 (1993):2812-2816) and to airway epithelium of rhesus monkeys (Bout et al., Gene Ther., 1 (1994):385-394; Bout et al., Hum. Gene Ther., 5(1994):3-10). In addition, the present inventors, their coworkers and others have observed a very efficient in vivo adenoviral vector mediated gene transfer into a variety of established solid tumors in animal models (lung tumors, glioma) and into human solid tumor xenografts in immune-deficient mice (lung) (Haddada et al., Biochem. Biophys. Res. Comm. 195 (1993):1174-1183; Vincent et al., Hum. Gene Ther., 7 (1996):197-205; reviewed by Blaese et al., Cancer Gene Ther., 2 (1995):291-297. Thus, preferred methods for in vivo gene transfer into tumor cells of nucleic acid molecules that encode molecules that can be used to kill said tumor cells make use of adenoviral vectors as gene delivery vehicles.
Said molecules that can be used to kill tumor cells include but are not restricted to suicide enzymes that convert a non-toxic prodrug into a toxic compound (e.g. the HSV-tk/ganciclovir system), cytokines, antisense nucleic acid molecules, ribozymes, and tumor suppressor proteins. In addition, treatment of cancer by gene therapy methods also includes the delivery of replicating vectors that are toxic to the tumor cells by themselves.
Gene therapy by introduction of nucleic acid molecules encoding suicide enzymes has been widely tested on a variety of tumor models. Especially the transfer of the Herpes simplex virus thymidine kinase (HSV-tk) gene into tumor cells in conjunction with systemic administration of the non-toxic substrate ganciclovir has proven to be an effective way of killing tumor cells in vivo (Esandi et al., Gene Ther., 4 (1997) :280-287; Vincent et al., J. Neurosurg., 85 (1996) :648-654; Vincent et al., Hum. Gene Ther., 7 (1996) :197-205). An important advantage of the HSV-tk/ganciclovir system is that upon ganciclovir treatment HSV-tk transduced tumor cells mediate a significant killing effect on neighboring untransduced tumor cells, the so-called bystander effect (Culver et al, Science 256 (1992) :1550-1552). Thus, using this approach there is no absolute need for gene transfer into every individual cell in a solid tumor to achieve successful gene therapy. A limitation of this approach, however, is that the effect remains local. Consequently, the HSV-tk gene needs to be delivered into every individual solid tumor or metastasis throughout the body.
Gene therapy for cancer by the introduction of nucleic acid molecules encoding cytokines is based on the concept of enhancing the immune response against the tumor cells. The ultimate goal of this approach is to obtain regression of the treated tumor and simultaneously induce such a high degree of immunity that c

LandOfFree

Say what you really think

Search LandOfFree.com for the USA inventors and patents. Rate them and share your experience with other people.

Rating

Interleukin-3 gene therapy for cancer does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Interleukin-3 gene therapy for cancer, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Interleukin-3 gene therapy for cancer will most certainly appreciate the feedback.

Rate now

     

Profile ID: LFUS-PAI-O-2967437

  Search
All data on this website is collected from public sources. Our data reflects the most accurate information available at the time of publication.