EP1218521A1 - Use of soluble costimulatory factor for tumor immuno-gene therapy - Google Patents
Use of soluble costimulatory factor for tumor immuno-gene therapyInfo
- Publication number
- EP1218521A1 EP1218521A1 EP00968693A EP00968693A EP1218521A1 EP 1218521 A1 EP1218521 A1 EP 1218521A1 EP 00968693 A EP00968693 A EP 00968693A EP 00968693 A EP00968693 A EP 00968693A EP 1218521 A1 EP1218521 A1 EP 1218521A1
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- EP
- European Patent Office
- Prior art keywords
- tumor
- cells
- vector
- factor
- cancer cells
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/70532—B7 molecules, e.g. CD80, CD86
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
Definitions
- This invention relates to a gene therapy for neoplasm, wherein a tumor cell is trasnduced with a gene encoding a soluble costimulatory factor.
- the transduced tumor cell secretes the costimulatory factor which induces T-cells to attack both transduced and untransduced cells of the tumor.
- APCs antigen presenting cells
- T-cells randomly interact by adhesion molecules, which are cell surface ligands and their respective receptors.
- the second interaction, recognition, will occur if the APCs can process, transport, and present sufficient quantities of the antigen within a major histocompatibility complex (MHC) molecule.
- MHC major histocompatibility complex
- the antigen-MHC is then recognized by the T-cell via the ligation (i.e. , binding and cross-linking) of the T-cell receptor complex (TCR) to the antigen-MHC.
- the third interaction, costimulation, is needed for T-cells to induce cellular proliferation, cytokine secretion, and effector function.
- the second and third interactions are respectively known as signal 1 and signal 2. If signal 2 is not delivered, T-cells enter anergy, a state of long-term unresponsiveness to specific antigens.
- the first signal is a tumor antigen, which is processed, transported to, and presented by MHC class I and/or class II molecules on the surface of APCs.
- the second signal is a costimulatory molecule present on tumor cells and/or other APCs (Mueller et al., 1989, Annu. Rev. Immunol. 7:445-480).
- Anergy or tolerance to tumor cells occurs as a result of CD8 + T-cells receiving the signal of a MHC- bound tumor antigen, but not a second signal of costimulatory molecules (Schwartz, 1993, Sci. Am. 269:48-54).
- Membrane proteins of the B7 family are known to be the most potent of the costimulatory molecules (Galea-Lauri et al. , 1996, Cancer Gene Ther. 3:202-213).
- the expression of a single costimulatory factor on the tumor cell membrane is ineffective in nonimmunogenic tumors, presumably due to the lack of coexpression of MHC-bound tumor antigen (Chen et al., 1994, J. Exp. Med. 179:523-532).
- the environment where an immune response is initiated can influence which types of cells become antigen presenting cells.
- dendritic cell, activated B cells, and monocytes serve as antigen presenting cells
- keratinocytes and Langerhans cells present antigens.
- "Professional" APCs are cells such as dendritic cells, activated B cells, and activated macrophages, which can process and present antigens on their surface. Professional APCs have been found to have the ability to present tumor antigens in association with an MHC molecule. Tumor cells also can serve as APCs. Huang et al.
- MHC class I-restricted tumor antigens usually are not presented by the tumor itself, but by dendritic cells or bone- marrow-derived APCs.
- Dendritic cells are capable of efficiently presenting antigen derived from apoptotic cells or virus-infected cells, stimulating class I-restricted CD8 + CTLs (Albert et al., 1998, Nature, 392:86-89).
- Dendritic cells that infiltrate tumors can lack B7 molecules and therefore have reduced T-cell stimulatory activity (Chaux et al., 1996, Lab. Invest., 74:975-983).
- the present invention addresses the problem of incomplete tumor antigen immunization by providing a gene therapy that entails delivering, to tumor cells, an expressible nucleotide sequence encoding a soluble costimulatory factor, thereby activating or enhancing the response of T-cells to a tumor.
- An "expressible nucleotide sequence” is a naturally occurring or man-made nucleotide sequence required for the production of a functional polypeptide.
- Figure 1 is a schematic representation of an amplicon plasmid containing a B7-1-Ig gene.
- Figure 2 is a graphic representation of the effect of dvB7-GPT on subcutaneous Neuro2a tumor growth in A/J mice.
- Figure 3 is a graphic representation of the effect of dvB7-GPT on the survival of A/J mice with intracerebral Neuro2a tumors.
- Figure 4 is a graphic representation of the lack of effect of dvB7-GPT on subcutaneous Neuro2a tumor growth in nude mice.
- the present invention overcomes the problem of T-cell anergy towards poorly immunogenic or nonimmunnogenic tumors. It is desirable to use soluble costimulatory factors such as B7-1 due to the limited ability of tumor cells to function effectively as APCs.
- the present invention by enabling the expression of a soluble costimulatory factor in the tumor environment, allows for T-cells to be activated in at least two ways.
- the presence of the soluble costimulatory factor provides dendritic cells and other APCs surrounding or infiltrating the tumor increased T-cell stimulation.
- the presence of soluble costimulatory factors in the tumor environment can assist tumor cells in functioning as APCs because most types of tumor cells do not express B7 molecules (Chen et al. , 1994, J. Exp. Med. , 179: 523-532; Denfeld et al. , 1995, Int. J. Cancer, 62:259-265).
- the first method of activation alone may suffice in inducing an immune response. Therefore, the second method of activation, antigen presentation by tumor cells themselves, may not be necessary.
- the presence of costimulatory factors may reverse me ⁇ nergic staie of primed T-cells to an activated state.
- the soluble costimulator is designed so that two extracellular domains are linked together. It has been shown that cross-linking of neighboring CD28, a counterreceptor on T-cells for the B7 molecule, is essential for T-cell activation (Schwartz et al. , 1993, Sci Am, 269:48-54). Hence, a dimeric soluble costimulatory factor should advantageously provide stronger stimulation to T-cells than monomeric factor normally expressed on the cell surface.
- a preferred linker for the extracellular domains is the Fc portion of immunoglobulin (Ig)G.
- a particularly preferred embodiment of the soluble costimulatory factor is B7-l-IgG.
- Localized delivery of a vector expressing soluble costimulatory factor is superior to systemic delivery of soluble costimulatory factor.
- local secretion offers an abundant amount of costimulatory factor to APCs that have processed tumor antigens in the tumor-surrounding environment, causing increased T- cell stimulatory activity with a specific direction to the tumor cells.
- soluble costimulatory factor secreted from tumor cells should activate local T-cells by reversing the anergic state.
- local vector administration causes soluble B7-1 to be expressed almost exclusively by tumor cells, therefore allowing tumors cells, but not other non- professional APCs, to function as APCs.
- Local vector administration can also provide higher concentration and more localized distribution of soluble costimulatory factor in the tumor and the surrounding region than systemic administration.
- systemic administration of soluble costimulatory factor may cause activation of T-cells primed to various types of antigens.
- Such a non-specific immune response may trigger immune responses against irrelevant antigens, or normal tissues or organs, potentially causing an undesirable toxicity or an autoimmune disease.
- Vector-mediated local administration of IL-12 has been shown to cause minimal side effects, whereas systemic administration of IL-12 has been found to be relatively toxic in humans.
- Tumor cells surgically obtained from a patient can be grown in culture, transduced with soluble costimulatory molecule gene, and injected subcutaneously into the same patient for tumor vaccination.
- tumor cell in this description denotes a neoplastic cell derived from, tor example, melanoma, pancreatic cancer, prostate carcinoma, head and neck cancer, breast cancer, lung cancer, colon cancer, ovarian cancer, renal cancer, neuroblastoma, squamous cell carcinoma, hepatoma, mesothelioma, and epidermoid carcinoma.
- a tumor cell in this context, may be a neoplastic cell derived from a brain tumor, for example, astrocytoma, oligodendroglioma, meningioma, neurofibroma, glioblastoma, ependymoma, Schwannoma, neurofibrosarcoma, medulloblastoma, germ cell tumor, chordoma, pineal tumor, choroid plexus papilloma, pituitary tumor, or vascular tumor.
- astrocytoma oligodendroglioma, meningioma, neurofibroma, glioblastoma, ependymoma, Schwannoma, neurofibrosarcoma, medulloblastoma, germ cell tumor, chordoma, pineal tumor, choroid plexus papilloma, pituitary tumor, or vascular tumor.
- Tumor-related cell refers to any non-tumor cell that is present within a tumor, such as an endothelial cell, an infiltrating immune cell, a connective tissue cell, a vasculature cell, or a neural cell.
- An immune modulator is any substance that alters an immune response, and preferably, stimulates an antigenic response.
- Immune modulators include cytokines, chemokines, and membrane-bound costimulatory molecules.
- using a soluble costimulatory factor is not limited to B7-1. Rather, other costimulatory factors that are normally expressed on the cell surface of APCs, such as B7-2, CD40, CD72, CD2, can be used. Other costimulatory factors which may be used include B7-3, CD40 ligand, CD70, CD24, LFA-3, CD48, 4- 1BB, 4- IBB ligand, LIGHT, ICAM-1 (CD54).
- costimulatory pathways work synergistically. Therefore, a combination of two or more different types of costimulatory molecules listed above (soluble or not) is more potent in stimulating the immune response than each costimulatory factor alone, for example, B7-1 and CD48 (Li et al. , 1996, J. Exp. Med., 183:639-44). Furthermore, it has been demonstrated in vivo that IL-12 (Rao et al., 1996, J. Immunol., 156:3357-3365; Zitvogel et al., 1996, Eur. Immunol. , 26: 1335-1341), interferon gamma (Katsanis et al., 1996, Cancer Gene Ther.
- GM-CSF GM-CSF
- ICAM-1 Cavallo et al. , 1995, Eur. J. Immunol., 25: 1154- 1162
- MHC class II Baskar et al., 1996, J. Immunol. 156:3821-3827; Heuer et al., 1996, Hum. Gene Ther. 7:2059-2068
- B7 molecules enhances the stimulation of antitumor immunity.
- the fusion does not have to involve IgG. Rather, any protein or peptide sequence that will allow two B7-1 molecules to cross-link their cognate receptors can be used.
- Vectors other than the HSV vector described above can be used. These include viral vectors such as herpes simplex virus, retrovirus, adenovirus, adeno-associate ⁇ virus, vaccinia virus, avipox virus, baculovirus, and reovirus, and others.
- viral vectors such as herpes simplex virus, retrovirus, adenovirus, adeno-associate ⁇ virus, vaccinia virus, avipox virus, baculovirus, and reovirus, and others.
- HSV vectors which can be employed include replication- competent HSV, replication- incompetent HSV, and HSV amplicon vectors with or without helper virus.
- Non-viral vectors as well as viral vectors can potentially be used.
- the immuno-gene therapy of the present invention can be applied to any type of solid tumor.
- Delivery can be by direct intra-tumoral inoculation or by systemic delivery, subject to the qualification discussed above.
- Systemic delivery includes delivery by intra-muscular, parenteral, oral, intra- venous, intra-arterial, intra-peritoneal, intra-dermal, and subcutaneous means.
- Herpes Simplex Virus Vector Construction Defective herpes simplex virus (HSV) vectors containing a soluble B7-1 gene were used to demonstate the effectiveness of soluble costimulatory factor in tumor immuno-gene therapy.
- the soluble B7-1 (B7-1-Ig) was designed as a fusion protein of the extracellular domain of murine B7-1 and the Fc portion of human IgGl .
- an amplicon plasmid containing the B7-1-Ig gene was designed and constructed (Fig. 1).
- the B7-1-Ig gene was initially cut out from the plasmid B7. l-plg. The gene was inserted into another plasmid (pCR3) so that it is driven by the cytomegalovirus (CMV) immediate early promoter. The entire cassette, including the B7-1-Ig gene, was then cut out to construct the amplicon.
- the amplicon also contains the Escherichia coli gpt gene encoding the enzyme xanthine/guanine phosphoribosyltransferase and is driven by the SV40 promoter.
- the gpt gene is used to select for a defective HSV.
- the replication of helper HSV is blocked, whereas the defective HSV expressing the gpt gene shows a resistance to mycophenolic acid.
- gpt is able to convert the non-toxic substrate 6-thioxanthine (6-TX) into the toxic metabolite 6- TX-triphosphate (Mroz et al., 1993, Hum. Gene Ther. 4:589-595).
- the defective HSV vector was generated using multimutated, conditionally- replicating HSV vector G207 as a helper virus and the mycophenolic acid/xanthine/ hypoxanthine growth regimen.
- the defective HSV vector (dvB7-GPT) stock used in the studies had a defective to helper ratio of about 1:40, based on immunohistochemical detection of murine B7-1.
- a defective HSV vector containing the alkaline phosphatase gene instead of B7-1-Ig gene (dvAP-GPT) was also generated as a control.
- EXAMPLE 2 In Vitro Expression of a Soluble Costimulatory Factor Expression of B7-1-Ig in cultured cells infected by dvB7-GPT was detected by several methods.
- Vero African green monkey kidney
- Neuro2a murine neuroblastoma
- MOI multiplicity of infection
- Fc human IgG
- conditioned medium collected from dvB7-GPT-infected Neuro2a cells (MOI — 3) 68 hours post-infection was found to contain 0.34 ng/ml of secreted B7-1-Ig.
- A/J mice harboring established subcutaneous (s.c.) Neuro2a tumors (approximately 6 mm in diameter) were treated with two intrarumoral inoculations of dvB7-GPT (2 x 10 5 plaque forming units (pfu) of helper virus). Inoculations were performed three days apart. A significant inhibition of tumor growth was observed compared with mock-infected extract (mock) or dvAP-GPT of the same dose (p ⁇ 0.01 versus mock and p ⁇ 0.05 versus dvAP-GPT at day 17, unpaired t test; Fig. 2).
- mice were injected intracerebrally with Neuro2a cells and treated five days later with a stereotactic inoculation of dvB7-GPT (6 x 10 5 pfu of helper virus) at the same coordinates.
- a significant prolongation of median survival was observed compared with mock or dvAP- GPT (p ⁇ 0.001 versus mock and p ⁇ 0.05 versus dvAP-GPT, Wilcoxon test; Fig. 3).
- Expression of B7-1-Ig in vivo was detected subcutaneously.
- Neuro2a tumors were harvested 2 days after dvB7-GPT inoculation and immunostained for human IgG (Fc).
- CD8 and Mac-3 abundant CD4 + T- cells and fewer CD8 + T-cells were observed in areas corresponding to dvB7-GPT infection, but were not observed in dvAP-GPT-inoculated s.c. tumors. Mac-3-positive macrophages were observed ubiquitously in both dvB7-GPT- and dvAP-GPT-inoculated tumors.
- mice (Balb/c nu/nu) harboring established s.c. Neuro2a tumors (approximately 6 mm in diameter) were treated with intratumoral inoculation of dvB7-GPT in exactly the same manner and dosage as were A/J mice, no significant effect on tumor growth was observed compared with mock or dvAP-GPT (Fig. 4).
- B7-1-Ig gene delivery into tumor results in efficient antitumor activity in immunocompetent animals, and the data support that the effect is mediated by a T-cell response.
- Survivors from the subcutaneous Neuro2a rechallenge study were further challenged with a subcutaneous injection of Sal/N, A/J-derived chemically-induced sarcoma cells (5 x 10 6 ). All mice cured by dvB7-GPT, as well as all six naive A/J mice used as controls, showed tumor formation at 4 weeks post-implantation. This finding indicates that the protective antitumor immunity was specific to the Neuro 2a cells.
- HSV vectors HSV amplicon vectors with helper HSV
- HSV-thymidine kinase or IL-12 can exhibit antitumor effects as effectively as other vectors (retrovirus, adenovirus) with the same transgenes (Miyatake et al., 1997, Cancer Gene Ther. 4:222-228; Toda et al., 1998, J. Immunol. 160:4457- 4464).
- the animal tumor model used to show the effect of soluble B7-1 was chosen because Neuro2a cells form intracerebral tumors as well as subcutaneous tumors reproducibly in A/J mice with a 100% take rate, the tumors are fast-growing, and the model has been used to study the effect of cell surface B7 molecules.
- Neuro2a is known as one of the most poorly immunogenic cell lines and, therefore, can be considered as one of the most difficult targets for immunogene therapy. Since the present invention is effective with the relatively non-immunogenic Neuro2a cells, one understands that it will be effective with more immunogenic tumors.
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Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US15778799P | 1999-10-05 | 1999-10-05 | |
US157787P | 1999-10-05 | ||
PCT/US2000/027405 WO2001025450A1 (en) | 1999-10-05 | 2000-10-05 | Use of soluble costimulatory factor for tumor immuno-gene therapy |
Publications (1)
Publication Number | Publication Date |
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EP1218521A1 true EP1218521A1 (en) | 2002-07-03 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP00968693A Withdrawn EP1218521A1 (en) | 1999-10-05 | 2000-10-05 | Use of soluble costimulatory factor for tumor immuno-gene therapy |
Country Status (5)
Country | Link |
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EP (1) | EP1218521A1 (en) |
JP (1) | JP2003511394A (en) |
AU (1) | AU7856800A (en) |
CA (1) | CA2386533A1 (en) |
WO (1) | WO2001025450A1 (en) |
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2000
- 2000-10-05 JP JP2001528602A patent/JP2003511394A/en active Pending
- 2000-10-05 EP EP00968693A patent/EP1218521A1/en not_active Withdrawn
- 2000-10-05 AU AU78568/00A patent/AU7856800A/en not_active Abandoned
- 2000-10-05 CA CA002386533A patent/CA2386533A1/en not_active Abandoned
- 2000-10-05 WO PCT/US2000/027405 patent/WO2001025450A1/en not_active Application Discontinuation
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WO2001025450A1 (en) | 2001-04-12 |
JP2003511394A (en) | 2003-03-25 |
AU7856800A (en) | 2001-05-10 |
CA2386533A1 (en) | 2001-04-12 |
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