Methods and compositions for localized agent delivery

Abstract

The invention provides compositions and methods for delivering agents to localized regions, tissues, or organs in vivo by conjugating agent-loaded nanoparticles to cells having homing capability. The agents may be therapeutic or diagnostic agents such as cancer chemotherapeutic agents and imaging agents respectively.

1 .- 19 . (canceled) 
     
     
         20 . A method for the treatment of cancer in a human subject, the method comprising:
 administering to the human subject a composition comprising
 a carrier T cell that homes to a tumor or a tissue in which tumor cells exist in the human subject; and 
 a biodegradable nanoparticle conjugated to the surface of the carrier T cell, wherein the nanoparticle comprises a polymer loaded with an immunostimulatory cytokine, 
   wherein, as the nanoparticle biodegrades in vivo, the immunostimulatory cytokine is released and acts upon the carrier T cell and/or other T cells in the tumor or tissue microenvironment to stimulate an immune response against the tumor cells.   
     
     
         21 . The method according to  claim 20 , wherein the immunostimulatory cytokine is selected from the group consisting of IL-2, IL-7, IL-15, IL-15 superagonist, IL-15/IL-15Rα complex, IL-12, IL-21, IFN-gamma, IFN-alpha, GM-CSF, and FLTs-ligand. 
     
     
         22 . The method according to  claim 20 , wherein the immunostimulatory cytokine is complexed with an Fc fusion protein. 
     
     
         23 . The method according to  claim 20 , wherein the carrier T cell is autologous to the human subject. 
     
     
         24 . The method according to  claim 20 , wherein the nanoparticle is noncovalently conjugated to the surface of the carrier cell. 
     
     
         25 . A method for the treatment of cancer in a human subject, the method comprising:
 administering to the human subject a composition comprising
 a carrier cell that homes to a target site in which cancer cells exist in the human subject; and 
 a biodegradable nanoparticle conjugated to the surface of the carrier cell, wherein the nanoparticle comprises a polymer loaded with an immunostimulatory agent, 
   wherein, as the nanoparticle biodegrades in vivo, the agent is gradually released and acts upon the carrier cell and/or lymphocytes in the target site microenvironment to stimulate an immune response against the cancer cells.   
     
     
         26 . An immunostimulatory composition for use in the treatment of cancer in a human subject, the composition comprising:
 a carrier cell that homes to a target site in which cancer cells exist in a human subject; and   a biodegradable nanoparticle conjugated to the surface of the carrier cell, wherein the nanoparticle comprises a polymer loaded with an immunostimulatory agent,   
       wherein biodegradation of the nanoparticle in vivo results in sustained release of the agent, and 
       wherein the released agent acts upon the carrier cell and/or other cells in the target site microenvironment to stimulate an immune response against the cancer cells. 
     
     
         27 . The composition according to  claim 26 , wherein the immunostimulatory agent is selected from the group consisting of a cytokine, cytokine superagonist, cytokine mutant, interleukin, antigen, adjuvant, small molecule, chemokine, antibody, single chain antibody, antibody fragment, TLR ligand, and nucleic acid. 
     
     
         28 . The composition according to  claim 26 , wherein the immunostimulatory agent comprises a cytokine selected from the group consisting of IL-2, IL-7, IL-15, IL-15 superagonist, IL-15/IL-15Rα complex, IL-12, IL-21, IFN-gamma, IFN-alpha, GM-CSF, and FLTs-ligand. 
     
     
         29 . The composition according to  claim 26 , wherein the immunostimulatory agent comprises a cytokine complexed with a fusion protein. 
     
     
         30 . The composition according to  claim 29 , wherein the fusion protein comprises an Fc. 
     
     
         31 . The composition according to  claim 29 , wherein the immunostimulatory agent comprises an IL-15 complexed with a soluble IL-15Rα-human Fc fusion protein. 
     
     
         32 . The composition according to  claim 26 , wherein the carrier cell is selected from the group consisting of a nucleated cell, lymphocyte, T cell, CD4+ T cell, CD8+ T cell, tumor-infiltrating T cell, cytolytic T cell, B cell, NK cell, NK T cell, hematopoietic progenitor cell. 
     
     
         33 . The composition according to  claim 26 , wherein the carrier cell is a T cell. 
     
     
         34 . The composition according to  claim 26 , wherein the carrier cell is a T cell engineered to express a chimeric antigen receptor. 
     
     
         35 . The composition according to  claim 26 , wherein the carrier cell is conjugated to a plurality of the biodegradable nanoparticles. 
     
     
         36 . The composition according to  claim 26 , wherein the nanoparticle is noncovalently conjugated to the surface of the carrier cell. 
     
     
         37 . The composition according to  claim 26 , wherein the nanoparticle is conjugated to the surface of the carrier cell through adsorption. 
     
     
         38 . The composition according to  claim 26 , wherein the polymer is loaded with one or more agents, and wherein one of the agents is the immunostimulatory agent. 
     
     
         39 . The composition according to  claim 26 , wherein the carrier cell is a CD8+ T cell, the immunostimulatory agent comprises a cytokine complexed with an Fc fusion protein; and the nanoparticle is noncovalently conjugated to the T cell.