JP2003511394A - Use of soluble costimulators for tumor immunity-gene therapy - Google Patents

Abstract

(57) [Summary] Novel gene therapy triggers tumor therapy by enhancing the T cell response to the tumor by introducing an expressible nucleotide sequence of a soluble costimulator. In vivo expression of this soluble factor overcomes anergy or tolerance to tumor cells and activates T cells that infiltrate or surround the tumor. Pharmaceutical compositions containing such genes are effective for tumor suppression.

Description

Detailed Description of the Invention

[0001] BACKGROUND OF THE INVENTION 1. Field 1. invention relates gene therapy the gene encoding the soluble costimulatory factor to tumor cells to neoplasms, characterized by transduction. Transduced tumor cells secrete costimulatory factors, which induce T cells to attack both transduced and non-transduced tumor cells.

2. Description of Related Art Inducing an antigen-specific immune response requires three distinct interactions between an antigen presenting cell (APC) and an antigen. The first interaction is adhesion. When APCs and T cells interact randomly with adhesion molecules, the adhesion molecules are cell surface ligands and their respective receptors. The second interaction, or cognition, is APC
Processes and transports a sufficient amount of antigen and transports the major histocompatibility complex (M
HC) would occur if it could be presented in the molecule. Antigen-MHC then
It is recognized by T cells through the link (ie, binding and cross-linking) of the cell receptor complex (TCR) and antigen-MHC. A third interaction, co-stimulation, is required for the induction of T cell proliferation, cytokine secretion and effector function. The second and third interactions are known as Signal 1 and Signal 2, respectively.
If signal 2 is not achieved, T cells enter the anergic state, a state of long-term unresponsiveness to specific antigens.

Induction of tumor-specific cytotoxic T lymphocytes (CTLs) requires the above two signals that should be present on APCs. The first signal is the 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 tumor cells and / or other APC
Is a co-stimulatory molecule present above (Mueller et al., 1989, Annu. Rev. Immunol. 7:44.
5-480). Anergy or tolerance to tumor cells occurs as a result of CD8 ⁺ T cells being signaled by MHC-bound tumor antigens but not the secondary signal of costimulatory molecules (Schwartz, 1993, Sci. Am. 269: 48-54).

The B7 family of membrane proteins are known to be the most potent of the costimulatory molecules (Galea-Lauri et al., 1996, Cancer Gene Ther. 3: 202-213). However, expression of a single costimulatory factor on the tumor cell membrane is not effective in non-immunogenic tumors. This is probably due to the lack of co-expression of MHC-binding tumor antigens (Chen et al., 1994, J. Exp. Med. 179: 523-532).

The environment in which the immune response is elicited can influence which cell type becomes the antigen presenting cell. For example, in peripheral blood, dendritic cells, activated B cells and monocytes function as antigen presenting cells, while in skin, keratinocytes and Langerhans cells present antigen. "Professional" APCs are cells such as dendritic cells, activated B cells and activated macrophages, which are capable of processing antigens and presenting them on their surface. "Professional" APCs were found to have the ability to present tumor antigens associated with MHC molecules. Tumor cells can also function as APCs.

[0006] Huang et al. (1994, Science, 264: 961-965), MHC class I-restricted tumor antigens are usually not presented by the tumor itself, but by dendritic cells or bone marrow-derived APCs. Dendritic cells can efficiently present antigens derived from apoptotic or virus-infected cells and stimulate class I-restricted CD8 ⁺ CTL (Albert et al., 199.
8, Nature, 392: 86-89). However, tumor-infiltrating dendritic cells may lack the B7 molecule and thus have reduced T cell stimulatory activity (Chaux et al., 1996, L
ab. Invest., 74: 975-983).

Current gene therapies for cancer control often fail because there is currently no genetic vector that can infect 100% of the tumor cells.
Therefore, these treatments have not resulted in total tumor destruction.

SUMMARY OF THE INVENTION The present invention provides gene therapy that delivers an expressible nucleotide sequence encoding a soluble co-stimulator to tumor cells, thereby causing activation or enhancement of a T cell response to the tumor. It addresses the problem of incomplete tumor antigen immunization. An "expressible nucleotide sequence" is a natural or synthetic nucleotide sequence required for the production of a functional polypeptide.

When soluble co-stimulators are expressed in the tumor or in adjacent regions of the tumor, anergy is overcome, T cell activation is stimulated, and activated T cells infiltrating or surrounding the tumor are immune responses to the tumor cells. To start. The co-stimulatory factors thus secreted induce the destruction of tumor cells whether or not they have been transformed with an expressible nucleotide sequence.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS By using a soluble co-stimulator, preferably a soluble co-stimulator of the B7 family (eg, B7-1), the present invention provides less immunogenic or immunogenic. Overcome the problem of T-cell anergy for tumors without tumors. The use of soluble costimulatory factors such as B7-1 is desirable because of the limited ability of tumor cells to function effectively as APCs.

The present invention enabled T cells to be activated in at least two ways by expressing soluble co-stimulatory factors in the tumor environment. First, the presence of soluble co-stimulatory factors causes dendritic cells and other APCs that surround or invade the tumor.
The increase in T cell stimulation is provided by. Second, since most tumor cell types do not express the B7 molecule, the presence of soluble co-stimulators in the tumor milieu can help tumor cells function as APCs (Chen et al., 1994, J. Exp. Med. , 179: 52
3-532; Denfeld et al., 1995, Int. J. Cancer, 62: 259-265). The first activation method alone may be sufficient to induce an immune response. Therefore, a second activation method, namely antigen presentation by the tumor cells themselves, may not be necessary. Furthermore, the presence of co-stimulatory factors can reverse primed T cells in anergic state to activated state.

[0012] In a preferred embodiment, the soluble costimulator is designed to link the two extracellular domains together. Counter-receptor (co
Cross-linking of adjacent CD28s (unterreceptors) has been shown to be essential for T cell activation (Schwartz et al., 1993, Sci Am, 269: 48-54). Therefore, dimeric soluble co-stimulators should be advantageous in providing more potent stimulation of T cells than the monomeric factors normally expressed on the cell surface. A preferred linker for the extracellular domain is the Fc portion of immunoglobulin (Ig) G. A particularly preferred embodiment of the soluble co-stimulator is B7-1-IgG.

Local delivery of the vectors expressing soluble co-stimulators of the present invention is superior to systemic delivery of soluble co-stimulators. For example, local secretion causes an increase in T cell stimulatory activity, which has a specific tropism for tumor cells, by providing large amounts of costimulatory factors to APCs that process tumor antigens in the peritumoral environment. Soluble co-stimulatory factors secreted by tumor cells are also activated by reversing local T cells from their anergic state. Furthermore, topical administration of the vector allows soluble B7-1 to be expressed almost exclusively by tumor cells, allowing them to function as APCs rather than other non-professional APCs. Topical vector administration can also provide a higher concentration and more localized distribution of soluble co-stimulators in the tumor and surrounding areas than systemic administration. On the other hand, systemic administration of soluble co-stimulators can cause activation of T cells primed with various serotypes. Such non-specific immune responses may elicit an immune response against unrelated antigens or normal tissues or organs, potentially causing unwanted toxicity or autoimmune disease. Vector-mediated topical administration of IL-12 was shown to cause minimal side effects, while systemic administration of IL-12 was found to be relatively toxic to humans.

The present invention can also be applied to tumor vaccination using the ex vivo method. Tumor cells surgically obtained from a patient can be grown in culture and transduced with a soluble co-stimulator gene, which can be injected subcutaneously into the same patient as a tumor vaccination.

The term “tumor cell” as used herein refers to, for example, melanoma, pancreatic cancer, prostate cancer, head and neck cancer, breast cancer, lung cancer, colon cancer, ovarian cancer, kidney cancer, neuroblastoma, squamous cell carcinoma. By neoplastic cells derived from cancer, liver cancer and mesothelioma and epidermoid carcinoma.
Tumor cells in this background include brain tumors such as astrocytoma, oligodendroma, meningiomas, neurofibromas, glioblastomas, ependymomas, schwannomas, neurofibrosarcomas. , Medulloblastoma, germinoma, chordoma, pineal tumor, choroid plexus papilloma, pituitary tumor or vascular tumor May be "Tumor associated cell" means any non-tumor cell present within a tumor and includes, for example, endothelial cells, infiltrating immune cells, connective tissue cells, vascular cells or nerve cells.

An immune activity modulator is any substance that alters the immune response and preferably stimulates an antigenic response. Immune activity modulators include cytokines, chemokines and membrane-bound costimulatory molecules.

According to the present invention, the use of soluble costimulators is not limited to B7-1. In addition, other costimulators normally expressed on the cell surface of APCs, such as B7-2, CD40
, CD72, CD2 can be used. Other costimulators that can be used include B7-3, CD40 ligand, CD70, CD24, LFA-3, CD48, 4-1BB, 4-1BB ligand, LIG.
HT, ICAM-1 (CD54) are included.

Furthermore, the various costimulatory pathways act synergistically. Therefore, the above costimulatory molecule
Combining two or more different forms (soluble or not) is more potent than stimulating the immune response with each costimulator alone, including, for example, the combination of B7-1 and CD48 ( Li et al., 1996, J. Exp. Med., 183: 639-44). Furthermore, IL-
12 (Rao et al., 1996, J. Immunol., 156: 3357-3365; Zitvogel et al., 1996, Eur. Immu.
nol., 26: 1335-1341), interferon gamma (Katsanis et al., 1996, Cancer Gene T.
her. 3: 75-82), GM-CSF (Parney et al., 1997, Hum. Gene Ther., 8: 1073-1085), I
CAM-1 (Cavallo et al., 1995, Eur. J. Immunol., 25: 1154-1162) or MHC class II
(Baskar et al., 1996, J. Immunol. 156: 3821-3827; Heuer et al., 1996, Hum. Gene Th.
er. 7: 2059-2068) was shown in vivo to enhance stimulation of anti-tumor immunity when expressed with the B7 molecule.

Moreover, the fusion need not include IgG. If anything, any protein or peptide sequence capable of bridging two B7-1 molecules to their cognate receptor can be used. Vectors other than the above HSV vectors can be used. These include herpes simplex virus, retrovirus, adenovirus,
Adeno-associated virus, vaccinia virus, avipoxvirus, baculovirus, reovirus and the like are included.

In addition, other HSV vectors that can be used are replication-competent (replicat
ion-competent HSV, replication-incompetent HSV, and HSV amplicon vectors with or without a helper virus.
Non-viral vectors can potentially be used as well as viral vectors.
The immuno-gene therapy of the present invention can be applied to any type of solid tumor.

Depending on the restrictions mentioned above, direct intratumoral inoculation or systemic delivery is possible. Systemic delivery includes delivery by intramuscular, parenteral, oral, intravenous, intraarterial, intraperitoneal, intradermal and subcutaneous methods.

The present invention is further described with reference to the following examples, which are set forth by way of illustration only. These examples should not be construed as limiting the overall scope of the invention.

[0023] with reference to examples Example 1 containing construct soluble B7-1 gene herpes simplex virus vectors deficient herpes simplex virus (HSV), tumor immunity - shows the effectiveness of the soluble costimulatory factor in gene therapy . Soluble B7-1 (B7
-1-Ig) was designed as a fusion protein of the extracellular domain of mouse B7-1 and the Fc portion of human IgG1. An amplicon plasmid containing the B7-1-Ig gene was designed and constructed to generate a deleted HSV vector (Figure 1).

First, the B7-1-Ig gene was excised from the plasmid B7.1-pIg. By inserting this gene into another plasmid (pCR3), the immediate early (immeme) of cytomegalovirus (CMV)
diate early) driven by the promoter. The entire cassette containing the B7-1-Ig gene was then excised to construct the amplicon. The amplicon also contains the E. coli gpt gene encoding the xanthine / guanine phosphoribosyl transferase enzyme and is driven by the SV40 promoter.

The gpt gene is used for selection of deleted HSV. In the presence of mycophenolic acid with xanthine and hypoxanthine, helper HSV replication is blocked, but deleted HSV expressing the gpt gene is resistant to mycophenolic acid. The deleted HSV thus obtained has a high ratio of deleted HSV to helper HSV. This method was used to study vaccinia virus (Falkner et al., 1988, J. Virol.
., 62: 1849-1854; Falkner et al., 1990, J. Virol., 64: 3108-3111) is a novel approach to the generation of deleted HSV vectors. An additional advantage of this vector is that gpt can convert the non-toxic substrate 6-thioxanthine (6-TX) to the toxic metabolite 6-TX-triphosphate (Mroz et al., 1993, Hum. Gene T
her. 4: 589-595).

The deletion HSV vector uses the HSV vector G207 as a helper virus to cause multiple mutations (multimutated), conditional replication, and a mycophenolic acid / xanthine / hypoxanthine growth method. It was made using. The ratio of deleted HSV to helper HSV in the deleted HSV vector (dvB7-GPT) stock solution used in this study was
Based on immunohistochemical detection of mouse B7-1 it was approximately 1:40. A deleted HSV (dvAP-GPT) containing an alkaline phosphatase gene in place of the B7-1-Ig gene was also prepared as a control.

Example 2 In Vitro Expression of Soluble Co- Stimulator The expression of B7-1-Ig in cultured cells infected with dvB7-GPT was detected by several methods. Vero (African green monkey kidney) cells and Neuro2a (mouse neuroblastoma)
Multiplicity of infection (MOI) of dvB7-GPT to each cell.
Immunohistochemical expression of B7-1-Ig was detected by antibodies against mouse B7-1 and human IgG (Fc) when infected with 25 and 3 (helper titer). When evaluated by enzyme-linked immunosorbent assay (ELISA) against human IgG, Neuro2a cells infected with dvB7-GPT (M
The conditioned medium recovered from OI = 3) 68 hours post infection was found to contain 0.34 ng / ml secreted B7-1-Ig.

[0028]Example 3 In vivo effects of soluble co-stimulators   A tumor model with immunocompetence of A / J mice and syngeneic Neuro2a cells for in vivo studies
I was there. In A / J mice with established subcutaneous (s.c.) Neuro2a tumors (diameter about 6 mm), dvB7-
Intratumoral injection of GPT (helper virus 2 x 10^FivePlaque forming unit
nits: pfu)) was treated twice. The inoculation at this time was performed every 3 days. Feeling mock
Presence of tumor growth when compared to stained extract (mock) or same dose of dvAP-GPT
Inhibition was observed (p <0.01 for mock and dvAP-GPT on day 17)
P <0.05, unpaired t test; Fig. 2). Neuro2a for A / J mice
Cells were injected intracerebrally and 5 days later at the same coordinates dvB7-GPT (helper virus 6 x 10 ^Five  pfu) was stereotactically inoculated. 50% survival days when compared to mock or dvAP-GPT
A significant prolongation of the number was observed (p <0.001 for mock and p <for dvAP-GPT
0.05, Wilcoxon test; Fig. 3).

In vivo expression of B7-1-Ig was detected subcutaneously. Neuro2a tumors were collected 2 days after inoculation of dvB7-GPT and immunostained for human IgG (Fc). Same tumor on CD4, CD8
And immunostaining for Mac-3, the presence of abundant CD4 ⁺ T cells and a smaller number of CD8 ⁺ T cells in the region corresponding to dvB7-GPT infection is observed, however, this result shows that dvAP -Not observed in sc tumors inoculated with GPT. Mac
-3 positive macrophages were observed to be ubiquitous in both dvB7-GPT and dvAP-GPT inoculated tumors.

Athymic nude mice (Balb / c nu / nu) with established sc Neuro2a tumors (diameter approximately 6 mm) were treated with dvB7-GPT in exactly the same manner and dose as A / J mice. When injected intratumorally, no significant effect on tumor growth was observed compared to mock or dvAP-GPT (Fig. 4). Thus, delivery of the B7-1-Ig gene to tumors elicits effective anti-tumor activity in immunocompetent animals. The data confirm that this effect is mediated by the T cell response.

In A / J mice with Neuro2a tumors deficient in CD8 ⁺ T cells, intratumor (intr
Aneoplastic) dvB7-GPT inoculation did not affect tumor growth and the antitumor activity of dvB7-GPT was completely abolished. In contrast, Neuro2a lacking CD4 ⁺ T cells
In tumor-bearing A / J mice, a significant inhibition of tumor growth was observed after dvB7-GPT inoculation (p <0.001 at day 13, unpaired t-test). Tumor growth inhibition was as effective as non-deficient animals, and CD4 ⁺ T cell deficiency itself had no effect on tumor growth. This indicates that the anti-tumor immune response induced by B7-1-Ig gene therapy requires CD8 ⁺ T cells, but not CD4 ⁺ T cells.

Five A / J mice were re-challenge with a lethal dose of Neuro2a tumor cells (this re-challenge of subcutaneous Neuro2a tumors was treated by intratumoral dvB7-GPT inoculation) without exception, in the early days. Tumor regression was caused after transient growth. All 6 naive (not all challenged) A / J mice used as controls showed continued tumor growth. Therefore, there is protective anti-tumor immunity after B7-1-Ig gene therapy according to the present invention.

Surviving mice from the subcutaneous Neuro2a rechallenge study were further challenged with a subcutaneous injection of chemically induced sarcoma cells (5 × 10 ⁶ ) derived from SaI / N, A / J. All dvB7-GPT treated mice as well as all 6 naive A / J mice used as controls showed tumor formation at 4 weeks post-implantation. This finding indicates that the protective antitumor immunity is N
It was shown to be specific to euro2a cells.

The neuroblastoma models described herein can be used to predict efficacy for other tumor types. Deletion HSV vector expressing HSV-thymidine kinase or IL-12 (
It has already been shown that HSV amplicon vectors with helper HSV can show similar effective anti-tumor effects as other vectors with the same transgene (retrovirus, adenovirus) (Miyatake et al., 1997, Cancer Gene T
her. 4: 222-228; Toda et al., 1998, J. Immunol. 160: 4457-4464). Neuro2a cells reproducibly form intracerebral tumors in addition to subcutaneous tumors in A / J mice at a rate of 100%, and further, the tumors grow rapidly, and animal tumor models show that the effect of cell surface B7 molecules The animal tumor model was selected to demonstrate the effects of soluble B7-1 as it has been used in studies.

Neuro2a cells transduced with B7-1 alone have been shown not to induce significant immunological protection even when 100% of the cells express B7-1 (Heuer et al., 1996, Hum. Gen
e Ther. 7: 2059-2068; Katsanis et al., 1995, Cancer Gene Ther. 2: 39-46), which is consistent with other poorly immunogenic tumors (Li et al., 1996, J. Exp. Med. ., 183
: 639-44; Chen et al., 1994, J. Exp. Med. 179: 523-532). Neuro2a is known to be one of the least immunogenic cell lines and can therefore be considered as one of the most difficult targets for immunogene therapy. The present invention has a relatively poor immunogenicity, Ne.
It is understood that, as effective against uro2a cells, it may also be effective against more immunogenic tumors.

[Brief description of drawings]

[Figure 1]   FIG. 1 is a schematic diagram of an amplicon plasmid containing the B7-1-Ig gene.

FIG. 2 is a graph relating to the effect of dvB7-GPT on the growth of subcutaneous Neuro2a tumors in A / J mice.

FIG. 3 is a graph relating to the effect of dvB7-GPT on the survival of A / J mice bearing intracerebral Neuro2a tumors.

FIG. 4 is a graph regarding the lack of dvB7-GPT effect on the growth of subcutaneous Neuro2a tumors in nude mice.

[Procedure amendment]

[Submission date] July 1, 2002 (2002.7.1)

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be amended] Claims

[Correction method] Change

[Contents of correction]

[Claims]

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 43/00 121 A61K 37/02 // C12N 15/09 C12N 15/00 A (81) Designated country EP ( AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, B Z, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS , JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Lovekin , Samuel, Dee. United States 20815 Maryland, Chevy Chase, North Park Avenue 4615 (72) Inventor Marts The, Robert, El. United States 20815 Chevy Chase, Maryland, Newlands Street 111 F Term (Reference) 4B024 AA01 CA01 EA02 GA11 HA17 4C084 AA01 AA02 AA13 DA01 DC50 NA05 NA14 ZB092 ZB262 4C087 AA01 AA02 BC83 NA05 NA14 ZB09 ZB26 ZB09 ZB26 ZB09

Claims (32)

[Claims] 1. A gene therapy method for activating or enhancing a T cell response in a patient having a tumor, comprising (A) a nucleotide sequence of a soluble co-stimulator capable of expression and (B)
Administration of a pharmaceutical composition comprising a vector to the patient, (i) the factor is expressed by tumor cells or tumor associated cells, and (ii) thereby activating or enhancing the T cell response to the tumor. The method comprising: 2. The method of claim 1, wherein the vector is targeted to tumor cells or tumor associated cells. 3. The method of claim 2, wherein the vector is a viral vector. 4. The viral vector comprises a retroviridae, a reoviridae,
The method according to claim 3, which is selected from the group consisting of adenoviridae, parvoviridae, herpesviridae, poxviridae, hepatitis delta virus and baculovirus. 5. The method of claim 2, wherein the vector is a non-viral vector. 6. The method according to claim 5, wherein the non-viral vector is a molecular conjugate vector or a synthetic virus. 7. The method of claim 1, wherein said administering comprises introducing the composition directly into the tumor or a localized area of the tumor. 8. The method of claim 7, wherein said administering comprises directly injecting the nucleotide sequence or the nucleotide sequence attached to a liposome carrier. 9. The method of claim 7, wherein the vector is a viral vector. 10. The viral vector is selected from the group consisting of retroviridae, reoviridae, adenoviridae, parvoviridae, herpesviridae, poxviridae, hepatitis delta virus and baculovirus.
The method of claim 8. 11. The method of claim 7, wherein the vector is a non-viral vector. 12. The factor is B7-1, B7-2, B7-3, CD40, CD40 ligand, CD72.
, CD24, LFA-3, ICAM-1, CD70, CD2, CD48, 4-1BB, 4-1BB ligand and LIGHT
The method of claim 1, selected from the group consisting of: 13. The method of claim 12, wherein the factor comprises two extracellular domains. 14. The method of claim 1, wherein the factor comprises an immunoglobulin Fc region. 15. The method of claim 1, wherein the factor comprises a dimer. 16. The method according to claim 15, wherein the monomers constituting the dimer are linked by a linker. 17. The method according to claim 1, wherein the vector is a viral vector. 18. The method of claim 1, wherein the vector is a non-viral vector. 19. The tumor is astrocytoma, oligodendroglioma, meningioma, neurofibroma, glioblastoma, ependymoma, schwannoma, neurofibrosarcoma, marrow The method according to claim 1, which is selected from the group consisting of blastoma, germinoma, chordoma, pineal tumor, choroid plexus papilloma, pituitary tumor and hemangiomas. 20. The tumor cells or tumor-related cells are melanoma cells, pancreatic cancer cells, prostate cancer cells, head and neck cancer cells, breast cancer cells, lung cancer cells, colon cancer cells, ovarian cancer cells, kidney cancer cells, neuroblasts. The method according to claim 1, wherein the method is selected from the group consisting of cell tumor, squamous cell carcinoma, liver cancer cell, and mesothelioma and epidermoid carcinoma cell. 21. The administration wherein at least one encodes an immune activity modulator.
2. The method further comprising delivering one expressible nucleotide sequence to the patient.
The method described in. 22. The method of claim 21, wherein the immune activity modulator is selected from the group consisting of cytokines, chemokines and membrane bound costimulatory molecules. 23. A pharmaceutical composition comprising (A) a vector containing a gene encoding a soluble co-stimulator and (B) a pharmaceutically compatible carrier. 24. A gene therapy method for activating or enhancing a T cell response in a patient having a tumor, said method comprising administering to said patient a pharmaceutical composition comprising a nucleotide sequence of an expressible soluble co-stimulator. The method, comprising (i) the factor being expressed by a tumor cell or a tumor-associated cell, and (ii) thereby activating or enhancing the T cell response to the tumor. 25. The method of claim 24, wherein said administering comprises introducing the composition directly into the tumor or a localized area of the tumor. 26. The factor is B7-1, B7-2, B7-3, CD40, CD40 ligand, CD72.
, CD24, LFA-3, ICAM-1, CD70, CD2, CD48, 4-1BB, 4-1BB ligand and LIGHT
25. The method of claim 24, selected from the group consisting of: 27. The method of claim 26, wherein the factor comprises two extracellular domains. 28. The tumor is astrocytoma, oligodendroglioma, meningioma, neurofibroma, glioblastoma, ependymoma of the ventricle, schwannoma, neurofibrosarcoma, marrow 25. The method of claim 24, which is selected from the group consisting of blastoma, germinoma, chordoma, pineal tumor, choroid plexus papilloma, pituitary tumor and hemangiomas. 29. The tumor cell or tumor-related cell is melanoma cell, pancreatic cancer cell, prostate cancer cell, head and neck cancer cell, breast cancer cell, lung cancer cell, colon cancer cell, ovarian cancer cell, kidney cancer cell, neuroblast. 25. The method of claim 24, wherein the method is selected from the group consisting of cell tumors, squamous cell carcinomas, hepatoma cells, and mesothelioma and epidermoid carcinoma cells. 30. The method of claim 24, wherein said administering comprises delivering to the patient at least one expressible nucleotide sequence encoding at least one immune activity modulator. 31. The method of claim 30, wherein the immune activity modulator is selected from the group consisting of cytokines, chemokines and membrane bound costimulatory molecules. 32. A pharmaceutical composition comprising (A) a gene encoding a soluble co-stimulator and (B) a pharmaceutically compatible carrier.