Modulated immunodominance therapy

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.

1 . A method for producing a culture expanded, cancer subdominant antigen responsive T cell population, the method comprising:
 contacting human T cells ex vivo with a plurality of fragments of a subdominant antigen from a cancer;   contacting the T cells with agents that promote antigen responsive T cell growth and expansion, comprising growth factors, hormones, immune cells and cytokines; and   enriching for the population of culture expanded subdominant antigen responsive T cells, wherein, the T cell population is capable of altering an immunodominance hierarchy in a patient having the cancer.   
     
     
         2 . The method of  claim 1 , wherein the human T cells are obtained from a tumor. 
     
     
         3 . The method of  claim 1 , wherein the human T cells are obtained from peripheral blood mononuclear cells (PBMC). 
     
     
         4 . The method of  claim 1 , further comprising the step of identifying a subdominant antigen in the cancer, prior to contacting human T cells with the fragments of the subdominant antigen. 
     
     
         5 . The method of  claim 1 , further comprising the step of identifying a subdominant antigen in a patient having the cancer, prior to contacting human T cells with the fragments of the subdominant antigen. 
     
     
         6 . The method of  claim 1 , wherein the fragments in the aggregate represent a full length form of the subdominant antigen. 
     
     
         7 . The method of  claim 1 , wherein the plurality of fragments do not include regions of the cancer subdominant antigen that evade antigen processing. 
     
     
         8 . The method of  claim 1 , wherein the culture expanded T cell population comprises multiple subpopulations, wherein each subpopulation is responsive to an individual fragment of the subdominant antigen. 
     
     
         9 . The method of  claim 1 , wherein the T cells are contacted with more than one subdominant antigen in the cancer. 
     
     
         10 . The method of  claim 9 , wherein the culture expanded T cell population is responsive to multiple cancer subdominant antigens. 
     
     
         11 . The method of  claim 1 , wherein the cancer is selected from the group consisting of: EBV malignancies, a carcinoma, a lymphoma, a blastoma, a sarcoma, a melanoma, a neuroblastoma, and a hepatocellular carcinoma. 
     
     
         12 . The method of  claim 1 , wherein the subdominant antigen is selected from the group consisting of: NY-ESO1, SSX-2, MAGE-A4, MAGE A1, Melan A, gp100, cancer related viral antigens, LMP1, LMP2, EBNA-1, HSV, HPV E6, HPV E7, HB core antigens, HB surface antigens, Hepatitis C antigens, HIV antigens, HTLV antigens and CMVpp65 antigens. 
     
     
         13 . The method of  claim 1 , wherein the subdominant antigen is a peptide, a protein or a nucleic acid. 
     
     
         14 . The method of  claim 3 , further comprising separating the PBMC into antigen presenting cells and T cells prior to contacting the T cells with the fragments of the subdominant antigen,
 wherein the T cells comprise naïve T cells, and   wherein the antigen presenting cells comprise monocytes, dendritic cells (DC) and macrophages.   
     
     
         15 . The method of  claim 1 , wherein the T cells do not comprise T cells responsive to a dominant antigen in the cancer. 
     
     
         16 . The method of  claim 1 , wherein the immune cells that promote antigen responsive T cell growth and expansion include antigen presenting cells stimulated by the subdominant antigen, wherein the antigen presenting cells are selected from monocyte derived dendritic cells, macrophages and EBV immortalized B cells. 
     
     
         17 . The method of  claim 1 , wherein the cytokines that promote antigen responsive T cell growth and expansion are selected from the group consisting of: IL-2, IL-4, IL-6, IL-7, IL-12, IL-15, IL-21, and any combination thereof. 
     
     
         18 . The method of  claim 17 , wherein the cytokines comprise IL-15, IL-2 or both. 
     
     
         19 . The method of  claim 18 , wherein the cytokines further comprise IL-7, IL-21 and IL-12. 
     
     
         20 . The method of  claim 1 , wherein the cytokines comprise a combination of any two or more cytokines selected from the group consisting of: IL-2, IL-7, IL-15 and IL-21. 
     
     
         21 . The method of  claim 20 , wherein,
 IL-2 is used at a concentration ranging between 2 Units(U)/ml and 1000 U/ml,   IL-7 is used at a concentration ranging between 1 ng/ml and 150 ng/ml,   IL-15 is used at a concentration ranging between 1 ng/ml and 150 ng/ml, or   IL-21 is used at a concentration ranging between 1 ng/ml and 150 ng/ml.   
     
     
         22 . The method of  claim 1 , the method further comprising the step of:
 confirming the presence of antigen responsive T cells by detecting in the culture expanded T cell population, cells with one or more T cell activation markers.   
     
     
         23 . The method of  claim 1 , wherein the culture expanded T cell population comprises CD8+ cytotoxic T cells responsive to the subdominant antigen. 
     
     
         24 . The method of  claim 1 , wherein the culture expanded T cell population comprises CD4+ T cells, TH1 and TH2 polarized CD4+ T cells responsive to the subdominant antigen. 
     
     
         25 . The method of  claim 1 , wherein the culture expanded T cell population comprises at least 5% cytotoxic T cells responsive to the cancer subdominant antigen. 
     
     
         26 . The method of  claim 1 , wherein the culture expanded T cell population comprises cytotoxic T cell subpopulations responsive to multiple cancer subdominant antigens.