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Vaccine composition comprising Flt3-ligand

Inactive Publication Date: 2006-12-28
IMMUNEX CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0008] The invention provides for the use of an effective amount of flt3-ligand to increase or mobilize the numbers of intermediate cells in vivo, for example, in the patient's peripheral blood or spleen. While the invention relates to the generation of large numbers of such downstream and intermediate cells (e.g., myeloid cells, monocytic cells and macrophages) from CD34+ cells using flt3-ligand, the focus is particularly on dendritic cells. By increasing the quantity of the patient's dendritic cells, such cells may themselves be used to present antigen to T cells. For example, the antigen may be one that already exists within the patient, such as a tumor antigen, or a bacterial or viral antigen. Flt3-L may be used, therefore, to increase the numbers of dendritic cells in vivo to boost a patient's immune response against existing antigens. The invention further provides for using combination therapy to enhance a patient's immune response. Such combination therapy includes administering flt3-ligand and one or more therapeutic reagents in amounts sufficiently effective to upregulate the patient's immune response. Alternatively, flt3-ligand may be administered prior to, concurrently with or subsequent to administration of an antigen to a patient for immunization purposes. Thus, as a vaccine adjuvant, flt3-ligand can generate large quantities of dendritic cells in vivo to more effectively present the antigen. The overall response is a stronger and improved immune response and more effective immunization to the antigen.
[0013] The invention also provides a method of augmenting an immune response in a patient that has a cancerous or neoplastic disease wherein the method comprises the step of administering an amount of flt3-ligand sufficient to increase the patient's number of dendritic cells. Embodiments of methods for augmenting an immune response include administering flt3-ligand in combination therapies with additional active compounds, including but not limited to CD40 binding proteins, 4-1BB-L, antibodies to 4-1BB, interferon alpha, RANKL, a CD30 ligand antagonist, and combinations thereof. Such method provides a means to enhance the patient's tumor-specific immune response.

Problems solved by technology

A frequent difficulty with active immunization protocols is that the vaccine antigen does not possess sufficient immunogenicity to promote a strong immune response, and therefore a sufficient level of protection against subsequent challenge by the same antigen.
The use of dendritic cells as immunostimulatory agents has been limited due to the low frequency of dendritic cells in peripheral blood, the limited accessibility to lymphoid organs and the dendritic cells' terminal state of differentiation.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Generation of Dendritic Cells

[0062] This Example describes a method for using flt3-ligand to generate large numbers of dendritic cells ex vivo. Cells having the CD34+ phenotype are isolated as described above, for example, first by generating a buffy coat of cells using a procedure described supra. Cells from the buffy coat are then incubated with a CD34 specific monoclonal antibody. The CD34+ cells which are selected then are cultured in McCoy's enhanced media with 20 ng / ml each of GM-CSF, IL-4, TNF-α, or 100 ng / ml flt3-ligand or c-kit ligand. The culture is continued for approximately two weeks at 37° C. in 10% CO2 in humid air. Cells then are sorted by flow cytometry for CD1a+ and HLA-DR+ expression. The combination of GM-CSF, IL-4 and TNF-α, resulted in a six to seven-fold increase in the number of cells obtained after two weeks of culture. The combination of flt3-ligand and c-kit ligand resulted in an additive 12-13-fold increase in absolute cell numbers. This correlated with ...

example 2

Use of Flt3-L in Dendritic Cell Expansion

[0063] This Example describes a method for using flt3-ligand for dendritic cell expansion. Prior to cell collection, it may be desirable to mobilize or increase the numbers of circulating PBPC and PBSC. Mobilization can improve PBPC and PBSC collection, and is achievable through the intravenous administration of flt3-ligand or sargramostim (Leukine®, Immunex Corporation, Seattle, Wash.) to the patients prior to collection of such cells. Other growth factors such as CSF-1, GM-CSF, c-kit ligand, G-CSF, EPO, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, GM-CSF / IL-3 fusion proteins, LIF, FGF and combinations thereof, can be likewise administered in sequence, or in concurrent combination with flt3-ligand. Mobilized or non-mobilized PBPC and PBSC are collected using apheresis procedures known in the art. See, for example, Bishop et al., Blood, vol. 83, No. 2, pp. 610-616 (1994). Briefly, PBPC and P...

example 3

Use of Flt3-L in Augmenting Anti-Tumor Immune Responses

[0065] This Example describes a method for using flt3-L to augment anti-tumor immune responses in vivo. Female C57BL / 10J (B10) mice (The Jackson Laboratory, Bar Harbor, Me.) were injected with 5×105 viable B10.2 fibrosarcoma tumor cells by intradermal injection in a midline ventral position in a total volume of 50 μl. The fibrosarcoma B10.2 line is of B10 origin and has been described previously, see Lynch et a., Euro. J. Immunol., 21:1403 (1991) incorporated herein by reference. The fibrosarcoma B10.2 line was induced by subcutaneous implantation of a paraffin pellet containing 5 mg of methylcholanthrene. The tumor cell line was maintained in vitro in α-modified MEM containing 5% FBS, 2 nM L-glutamine, 50 U / ml penicillin and 50 μg / ml streptomycin. Recombinant human flt3-L (10 μg / injection) was administered on a daily basis over a 19-day period (unless otherwise noted) by subcutaneous injection in a total volume of 100 μl. Cont...

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Abstract

Flt3-ligand can be used to generate large numbers of dendritic cells from hematopoietic progenitor and stem cells. Flt3-ligand can be used to augment immune responses in vivo, and expand dendritic cells ex vivo. Such dendritic cells can then be used to present tumor, viral or other antigens to naive T cells, can be useful as vaccine adjuvants. When flt3-L is used and / or administered in combination with other reactive agents, e.g. CD40 binding proteins, 4-1BBL or antibodies reactive with 4-1BB, CD30 ligand antagonists, RANKL, and / or interferon alpha the combination further enhances immune responses and the effectiveness of vaccine adjuvants.

Description

RELATED APPLICATIONS [0001] This application is a Continuation application of pending prior application Ser. No. 10 / 397,687 (Conf. No. 7724) filed Mar. 25, 2003; which is a Divisional of U.S. application Ser. No. 10 / 241,927, filed Sep. 11, 2002; which is a Continuation of U.S. application Ser. No. 09 / 444,027, filed Nov. 19, 1999 (now abandoned); which is a Continuation-In-Part of U.S. application Ser. No. 09 / 154,903, filed Sep. 17, 1998 (now abandoned); which is a Continuation-In-Part of U.S. application Ser. No. 08 / 725,540, filed Oct. 3, 1996 (now abandoned); which is a Continuation-In-Part of U.S. application Ser. No. 08 / 539,142, filed Oct. 4, 1995 (now abandoned); the disclosure of each of which is incorporated herein by reference.FIELD OF THE INVENTION [0002] The present invention relates to a dendritic cell stimulatory factor, to methods of enhancing an immune response in vivo, methods of expanding dendritic cells ex vivo, and to preparations of purified dendritic cells, and to...

Claims

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Application Information

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IPC IPC(8): A61K39/12A61K39/02A61K39/00A61K38/18A61K39/39C12N5/0784
CPCA61K38/18A61K39/0011C12N2506/30A61K39/39A61K2039/505A61K2039/5154A61K2039/55516A61K2039/55522C12N5/0639C12N2501/125C12N2501/22C12N2501/23C12N2501/24C12N2501/26A61K2300/00A61K39/4615A61K39/4622A61K39/464436
Inventor LYNCH, DAVIDBORGES, LUISMILLER, ROBERTMALISZEWSKI, CHARLES
Owner IMMUNEX CORP
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