Modulated Immunodominance Therapy

a technology of immunodominance and immunomodulation, applied in the field of cancer, chronic infections, autoimmune diseases, transplantation, etc., can solve the problems of unfavorable primary immunosuppressive environment and inability to create a profile of immune response on a routine clinical basis, so as to alter the immunodominance hierarchy of patients and alter the immunodominance hierarchy

Inactive Publication Date: 2014-04-10
GENEIUS BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0009]Disclosed is a novel approach to rebalance the immune response to antigens to provide significant therapeutic benefit in, among others, cancer, chronic and latent infection, autoimmunity and transplantation. By generating immune responses to subdominant epitopes and subdominant antigens in a controlled microenvironment, the invention fundamentally changes the nature of the immune response to the disease to one that provides therapeutic benefit. It can change the balance of the immune response before or after a prior immune response has occurred to the antigen or even if there is one ongoing.
[0010]The present invention features a method comprising i...

Problems solved by technology

However, creating a profile of the immune response has not been done on a routine clinical basis.
It is also well known tha...

Method used

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  • Modulated Immunodominance Therapy
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  • Modulated Immunodominance Therapy

Examples

Experimental program
Comparison scheme
Effect test

example 1

1. Example 1

EBV Latent Infection, Lymphomas and Nasopharyngial Carcinoma

[0161]90% of the world's population has been exposed to EBV (the causative virus in mononucleosis) as measured by antibodies in the blood. EBV becomes latent in B cells and shuts off the majority of its proteins but express very low levels of latent antigens LMP1, LMP2 and sometimes EBNA-1. These proteins are weakly immunogenic but are required to maintain the virus even in its latent state. Because they derive predominantly from B cells, 40% of lymphomas test positive for EBV latent antigens. Thus, these antigens can serve as targets for the generation of CTL responses in adoptive cell therapy. In addition, Nasopharyngial carcinoma also expresses EBV latent antigens as do other tumors (e.g. −10% of gastric cancer). While CTL's have been used to treat EBV lymphomas, the current production methods are time consuming (3-6 months) and cumbersome using B cells transformed with EBV as repeat stimulation. Further, CTL...

experiment 1

a. Experiment 1

The Relative Frequency of T Cells Responding to Subdominant Epitopes is Enhanced when Dendritic Cells or Activated Macrophages are Used as Antigen Presenting Cells Instead of LCL

[0166]T cell lines were prepared from 10 patients using 3 different antigen presenting cells as stimulators: EBV transformed lymphoblastoid cell lines (LCL) presentation and expansion; Dendritic cell (DC) presentation with cytokine expansion; IFNγ Macrophage (MAC) presentation with cytokine expansion. Each of the 3 were stimulated during antigen presentation with a mixture of 3 plasmids expressing subdominant epitopes of EBNA-1 (EBNA-1 with deletion of aa 90 to 325), LMP1 (LMP1 with deletion of aa 1-43 and aa 260-315) and LMP2 (LMP2A in 2 plasmids one expressing aa 1-399 and the second plasmid expressing aa 400-497). The T cell lines so generated using the protocol of the invention were then studied in 51Cr release assay.

[0167]FIGS. 1A and 1B: 51Cr release at two different effector:target (E / T...

example 2

b. Example 2

[0191]In the following experiments, T cells were grown in the same way as outlined in Example 1 above, with different variations designed to enhance antigen processing to favor T cells reactive with the production of subdominant epitopes.

[0192]FIG. 7: (51Cr release) Cr release at 20:1 effector:target (E / T) ratios (CTL Lines: HLA matched fibroblasts) HLA matched fibroblasts pre-pulsed with peptides representing Dominant antigen (EBNA-3A), Subdominant antigen (LMP2) and specific HLA A2 restricted subdominant epitopes from LMP2 with CTLs made from the same patient using two different methods: one with 100 nM to 300 nM bortezomib added during antigen presentation, one without.

[0193]Conclusion: Addition of the Proteosome antagonist bortezomib during CTL antigen presentation modifies antigen processing to generate CTL's to a broader number of subdominant epitopes with a modest decrease in the response to dominant epitopes

[0194]FIG. 8: (51Cr release) Cr release at 20:1 effector...

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Abstract

The invention involves generating a T cell response to subdominant antigens and using the cells to therapeutically change the cellular homeostasis and nature of the immune response. In a preferred embodiment, the cells are generated outside of the patient avoiding the influence of the patient's immunologic milieu. By stimulating and growing the T cells from a patient in a tissue culture to one or more subdominant antigens and the transplanting them into the patient, if enough cells are expanded and transplanted, the transplanted cells overwhelm the endogenous dominant T cells in the response to either break or induce immune tolerance or otherwise modify the immune response to the cells or organism expressing that antigen. When the memory cells are established they are then reflective of this new immunodominance hierarchy so that the desired therapeutic effect is long lasting. In effect, the transplantation exogenously generated T cells reactive to the subdominant antigens is recapitulating priming and rebalancing the patient's immune response to target previously subdominant antigens in the cells or organism to produce a therapeutic benefit.

Description

RELATED APPLICATIONS[0001]This application is a national stage application, filed under 35 U.S.C. §371, of International Application No. PCT / US2012 / 039605, filed on May 25, 2012, which is related to provisional application U.S. Ser. No. 61 / 490,505, filed on May 26, 2011, the contents of which are hereby incorporated by reference in its entirety.BACKGROUND OF THE INVENTION[0002]The present invention relates to a novel therapeutic for cancer, chronic infections, autoimmune diseases, and transplantation based upon the modification of the immunodominance hierarch by therapeutic manipulation of cellular homeostasis.[0003]The clinical management of cancer is specific for each site of origin and, for the most part, depends upon stage of the disease (i.e., how far the tumor has invaded locally or spread to other organs by metastasis). Surgery and / or localized radiotherapy are generally the treatment of choice for the primary tumor with chemotherapy, monoclonal antibody or cytokine therapy o...

Claims

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Application Information

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IPC IPC(8): A61K35/14A61K39/00
CPCA61K35/17A61K39/292C12N2730/10134A61K39/12A61P29/00A61P35/00A61P37/00A61P37/02A61P37/06C12N5/0636A61K39/4611C12N2502/1157C12N2502/1121C12N2501/2302C12N2501/2307A61K39/464838C12N2710/16011C12N2501/999A61K2239/53A61K2239/31A61K39/00A61K39/245A61K39/29C12N5/06C12N5/0617A61K39/0011A61K2039/55566A61K39/0008A61K2039/5158A61K2039/53A61K2039/585C12N2710/16034C12N2730/10171C12N7/00C12N2710/16234A61K9/0019C12N2501/2304C12N2501/2306C12N2501/2312C12N2501/2315C12N2501/2321A61K9/0021A61K2035/124
Inventor SLANETZ, ALFRED E.
Owner GENEIUS BIOTECH
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