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 of treating a cancer in a patient, the method comprising:
 a. identifying at least one subdominant antigen in the cancer;   b. producing a T cell population by cultivating T cells responsive to the at least one subdominant antigen; and   c. treating the patient with an effective number of cultivated T cells from the population to alter the immunodominance hierarchy in the patient, whereby the cancer in the patient is treated.   
     
     
         2 . The method of  claim 1 , wherein the T cell population comprises CD8+ cytotoxic T cells. 
     
     
         3 . The method of  claim 1 , wherein the T cell population comprises CD4+ T cells. 
     
     
         4 . The method of  claim 1 , wherein the T cell population comprises CD8+ and CD4+ T cells, wherein the cultivated T cells express T cell activation markers. 
     
     
         5 . The method of  claim 1 , wherein step (b) comprises the steps of:
 contacting human T cells ex vivo with a plurality of fragments of the at least one subdominant antigen in the cancer;   contacting the T cells with agents that promote antigen responsive T cell growth, comprising growth factors, hormones, cytokines, IL-2, IL-7, IL-15, IL-21, or any combination thereof, to produce a subdominant antigen responsive, activated T cell population; and   enriching for the subdominant antigen responsive, activated T cell population in culture, wherein the T cell population is responsive to the at least one subdominant antigen in cancer.   
     
     
         6 . The method of  claim 5 , wherein the T cells are present in human peripheral blood mononuclear cells (PBMC). 
     
     
         7 . The method of  claim 5 , wherein the human T cells are contacted with fragments of more than one subdominant antigen. 
     
     
         8 . The method of  claim 1 , wherein the patient is treated with a cultivated T cell population responsive to more than one cancer subdominant antigen. 
     
     
         9 . A method of treating a cancer in a patient, the method comprising:
 identifying at least one subdominant antigen in the cancer in the patient;   contacting human PBMC ex vivo with a plurality of fragments of the at least one subdominant antigen;   contacting the PBMC with agents that promote antigen responsive T cell growth, comprising growth factors, hormones, cytokines, IL-2, IL-7, IL-15, IL-21, or any combination thereof, to produce a subdominant antigen responsive T cell population;   enriching for the subdominant antigen responsive T cell population in culture;   administering to the patient an effective number of enriched T cells from the population to alter an immunodominance hierarchy in the patient; and   profiling the patient to determine if the immunodominance hierarchy in the patient is successfully altered,   thereby treating the cancer in the patient.   
     
     
         10 . The method of  claim 9 , wherein the plurality of the fragments of the subdominant antigen represent in the aggregate the full length form of the at least one subdominant antigen. 
     
     
         11 . The method of  claim 9 , wherein the fragments of the at least one subdominant antigen do not include regions of the antigen that evade antigen processing. 
     
     
         12 . The method of  claim 9 , wherein the PBMC are contacted with the fragments of the subdominant antigen in the absence of T cells responsive to a dominant antigen in the patient. 
     
     
         13 . The method of  claim 9 , further comprising, confirming that at least 5% of cells in the antigen responsive T cell population are cytotoxic to the at least one cancer subdominant antigen prior to administering the T cells to the patient. 
     
     
         14 . The method of  claim 9 , wherein the T cells from the population are administered to the patient, by a suitable administration route selected from intradermal and intravenous administration. 
     
     
         15 . The method of  claim 9 , wherein the patient is administered the effective number of T cells from the population more than once. 
     
     
         16 . The method of  claim 1 , wherein the effective number of T cells is between 10 8  and 10 12  cells. 
     
     
         17 . The method of  claim 9 , wherein enriching the antigen responsive T cell population in culture comprises sorting the population of cells based on presence or absence of T cell activation markers on the surface of the cells in the population, and isolating the effective number of the T cells into an isotonic buffer comprising a pharmaceutical composition suitable for intravenous administration to the patient. 
     
     
         18 . A method of treating an infection in a patient, the method comprising:
 a. identifying at least one subdominant antigen in the infection;   b. producing a T cell population by cultivating T cells capable of recognizing the at least one subdominant antigen; and   c. treating the patient with an effective number of the cultivated T cells to alter the immunodominance hierarchy in the patient, whereby the infection in the patient is treated.   
     
     
         19 . The method of  claim 18 , wherein step (b) comprises of the steps of:
 contacting human PBMC ex vivo with a plurality of fragments of the at least one subdominant antigen;   contacting the PBMC with agents that promote antigen responsive T cell growth, comprising growth factors, hormones, cytokines, IL-2, IL-7, IL-15, IL-21, or any combination thereof, to produce a subdominant antigen responsive T cell population; and   enriching for the subdominant antigen responsive T cell population in culture, thereby producing a culture enriched, subdominant antigen responsive T cell population, wherein the culture enriched, subdominant antigen responsive T cell population recognizes the at least one subdominant antigen.   
     
     
         20 . The method of  claim 19 , wherein the plurality of fragments of the subdominant antigen represent in the aggregate the full length form of the at least one subdominant antigen. 
     
     
         21 . The method of  claim 19 , wherein the fragments of the at least one subdominant antigen do not include regions of the antigen that evade antigen processing. 
     
     
         22 . The method of  claim 18 , wherein the culture enriched, subdominant antigen responsive T cell population comprises CD8+ cytotoxic T cells. 
     
     
         23 . The method of  claim 18 , wherein the culture enriched, subdominant antigen responsive T cell population comprises CD4+ T cells. 
     
     
         24 . The method of  claim 18 , wherein the culture enriched, subdominant antigen responsive T cell population comprises CD8+ and CD4+ T cells, the culture enriched, subdominant antigen responsive T cell population further expressing T cell activation markers. 
     
     
         25 . The method of  claim 18 , wherein the PBMC are contacted with more than one subdominant antigen in the infection. 
     
     
         26 . A method of treating an infection in a patient, the method comprising the steps of:
 identifying at least one subdominant antigen in the infection in the patient;   contacting human PBMCs ex vivo with a plurality of fragments of the at least one subdominant antigen, the fragments representing in the aggregate the full length form of the antigen;   contacting the PBMCs with agents that promote antigen restricted T cell growth, comprising growth factors, hormones, cytokines, IL-2, IL-7, IL-15, IL-21, or any combination thereof, to produce an antigen responsive, activated T cell population;   enriching the antigen responsive, activated T cell population in culture;
 administering to the patient an effective number of T cells from the population to induce a cytotoxic immune reaction to the infection in the patient which alters the immunodominance hierarchy in the patient; and 
 profiling the patient to determine if the immunodominance hierarchy in the patient is successfully altered, thereby treating the infection in the patient. 
   
     
     
         27 . The method of  claim 26 , wherein the patient is administered the effective number of the T cells more than once, wherein, an effective number of T cells comprise between 0.01% to 20% cytotoxic T cells responsive to the at least one subdominant antigen. 
     
     
         28 . The method of  claim 26 , where at least 5% of the cells in the antigen responsive, activated T cell population are responsive to the at least one subdominant antigen prior to administering the T cells to the patient. 
     
     
         29 . The method of  claim 26 , wherein treating the infection in the patient alters a chronic infection to an acute infection, thereby clearing the infection and treating the patient. 
     
     
         30 . The method of  claim 26 , wherein the effective number of T cells administered is between 10 6  and 10 12  cells. 
     
     
         31 . The method of  claim 26 , wherein the antigen responsive, activated T cell population comprises CD8+ and CD4+ T cells, the T cells in the antigen responsive, activated T cell population further expressing T cell activation markers. 
     
     
         32 . The method of  claim 26 , wherein enriching the antigen responsive, activated T cell population in culture comprises sorting cells in the population based on presence or absence of T cell activation markers on the surface of cells in the antigen responsive, activated T cell population, and isolating an effective number of the T cells from the population to induce a cytotoxic immune reaction to the infection in the patient into an isotonic buffer comprising a pharmaceutical composition suitable for intravenous administration to the patient.