Immunoswitch nanoparticles for reprogrammed t cell responses

Abstract

The presently disclosed subject matter relates to immunoswitch particles that switch off immunosuppressive pathways on tumor cells or immunosuppressive molecules induced by tumor cells in the tumor microenvironment, or virus infected cells or immunosuppressive molecules induced by virus infected cells in the microenvironment surrounding the virus infected cells, while simultaneously switching on co-stimulatory or co-inhibitory pathways on T cells, as well as method for converting immunosuppressive infections.

1 . An immunotherapy method of treating a cancer or a chronic viral infection in a subject in need thereof, the method comprising administering an effective amount of an immunoswitch particle to the subject,
 wherein the immunoswitch particle comprises a nanoparticle comprising a first agent that targets an immunosuppressive pathway in a tumor cell or an immunosuppressive molecule induced by the tumor in the tumor microenvironment, or the first agent targets a virus infected cell or an immunosuppressive molecule induced by the virus infected cell in microenvironment surrounding the virus infected cell, and a second agent that targets a co-stimulatory or co-inhibitory pathway in a T cell, thereby simultaneously targeting in the subject the immunosuppressive pathway in the tumor cell or tumor microenvironment, or the virus infected cell or microenvironment surrounding the virus infected cell, and the co-stimulatory or co-inhibitory pathway in the T cell,   wherein simultaneously targeting the immunosuppressive pathway in the tumor cell or tumor microenvironment, or virus infected cell or microenvironment surrounding the virus infected cell, and the co-stimulatory or co-inhibitory pathway in the T cell enhances the subject's immune system and treats the cancer or chronic viral infection in the subject.   
     
     
         2 . An immunoswitch particle comprising a nanoparticle comprising a first agent that targets an immunosuppressive pathway in a tumor cell or immunosuppressive molecule induced by the tumor cell in the tumor microenvironment, or a virus infected cell or immunosuppressive molecule induced by the virus infected cell in the microenvironment surrounding the virus infected cell, and a second agent that simultaneously targets a co-stimulatory pathway or co-inhibitory pathway in a T cell. 
     
     
         3 . A method of converting an immune inhibitory signal in a subject in need thereof into an immune stimulatory signal comprising administering an effective amount of the immunoswitch particle of  claim 2  to the subject, wherein the first agent targets the immunosuppressive pathway in the tumor cell or immunosuppressive molecule induced by the tumor cell in the tumor microenvironment, or virus infected cell or immunosuppressive molecule induced by the virus infected cell in the microenvironment surrounding the virus infected cell in the subject, and the second agent simultaneously targets the co-stimulatory pathway or co-inhibitory pathway in the subject's T cells, thereby converting an immune inhibitory signal in the subject into an immune stimulatory signal. 
     
     
         4 . The method of  claim 1  or the particle of  claim 2 , wherein:
 (i) the first agent targets the immunosuppressive pathway in a tumor cell and the method inhibits growth of the subject's tumor compared to growth of the subject's tumor in the absence of administration of the immunoswitch particle; or 
 (ii) the first agent targets the immunosuppressive pathway in virus infected cells and the method inhibits multiplicity of infection of the virus infected cells compared to the multiplicity of infection of the viral infected cells in the absence of administration of the immunoswitch particle. 
 
     
     
         5 . The method of  claim 1  or the particle of  claim 2 , wherein:
 (i) the first agent targets the immunosuppressive pathway in a tumor cell and the method extends the length of survival of the subject compared to length of survival of the subject in the absence of administration of the immunoswitch particle; or 
 (ii) the first agent targets the immunosuppressive pathway in a virus infected cell and the method extends latency of the virus in the subject compared to latency of the virus in the subject in the absence of administration of the immunoswitch particle. 
 
     
     
         6 . The method or particle of any one of the above claims, wherein the first agent comprises an agent that targets an immune checkpoint receptor. 
     
     
         7 . The method or particle of  claim 6 , wherein the immune checkpoint receptor is selected from the group consisting of PDL1 and PDL2. 
     
     
         8 . The method or particle of  claim 7 , wherein the first agent comprises an antibody or functional fragment thereof conjugated to the nanoparticle, wherein the antibody is selected from the group consisting of a PDL1 antagonist antibody or functional variant thereof, a PDL2 antagonist antibody or functional variant thereof, and combinations thereof. 
     
     
         9 . The method of any one of  claims 1 - 8 , wherein:
 (i) the T cell co-stimulatory pathway is selected from the group consisting of the 4-1BB signaling pathway, the CD27 signaling pathway, the CD28 signaling pathway, the ICOS signaling pathway, the CD226 signaling pathway, the CRTAM signaling pathway, the TIM1 signaling pathway, the CD2 signaling pathway, the SLAM signaling pathway, the CD84 signaling pathway, the Ly9 signaling pathway, the Ox40 signaling pathway, and the CRACC signaling pathway; or   (ii) the T cell co-inhibitory pathway is selected from the group consisting of the CTLA4 signaling pathway, the PD1 signaling pathway, the PD1H signaling pathway, the BTLA signaling pathway, the B71 signaling pathway, the PDL1 signaling pathway, the TIGIT signaling pathway, the TIM2 signaling pathway, the TIM3 signaling pathway, the LAIR1 signaling pathway, the LAG3 signaling pathway, and the CD160 signaling pathway.   
     
     
         10 . The method or particle of any one of  claims 1 - 9 , wherein the second agent comprises:
 (i) an antibody or functional variant thereof conjugated to the nanoparticle, wherein the antibody is selected from the group consisting of a 4-1BB agonist antibody or functional variant thereof, a CD27 agonist antibody or a functional variant thereof, a CD28 agonist antibody or functional variant thereof, a ICOS agonist antibody or functional variant thereof, a CD226 agonist antibody or functional variant thereof, a CRTAM agonist antibody or functional variant thereof, a TIM1 agonist antibody or functional variant thereof, a CD2 agonist antibody or functional variant thereof, a SLAM agonist antibody or functional variant thereof, a CD84 agonist antibody or functional variant thereof, a Ly9 agonist antibody or functional variant thereof, an Ox40 agonist antibody or functional variant thereof, a CRACC agonist antibody or functional variant thereof, and combinations thereof; or   (ii) a CTLA4 antagonist antibody or functional variant thereof, a PD1 antagonist antibody or functional variant thereof, a PD1H antagonist antibody or functional variant thereof, a BTLA antagonist antibody or functional variant thereof, a B71 antagonist antibody or functional variant thereof, a PDL1 antagonist antibody or functional variant thereof, a TIGIT antagonist antibody or functional variant thereof, a TIM2 antagonist antibody or functional variant thereof, a TIM3 antagonist antibody or functional variant thereof, a LAIR1 antagonist antibody or functional variant thereof, a LAG3 antagonist antibody or functional variant thereof, a CD160 antagonist antibody or functional variant thereof, and combinations thereof.   
     
     
         11 . The method or particle of any one of  claims 1 - 10 , wherein the first agent is a PDL1 antagonist antibody and the second agent is a 4-1BB agonist antibody. 
     
     
         12 . The method or particle of any one of  claims 1 - 10 , wherein the first agent is a PDL1 antagonist antibody and the second agent is a CD28 agonist antibody. 
     
     
         13 . The method or particle of any one of  claims 1 - 10 , wherein the first agent is a CD73 antagonist antibody and the second agent is a 4-1BB agonist antibody. 
     
     
         14 . The method or particle of any one of  claims 1 - 10 , wherein the first agent is a PD-L1 antagonist antibody and the second agent is a CD27 agonist antibody. 
     
     
         15 . The method or particle of any one of  claims 1 - 10 , wherein the first agent is a CD73 antagonist antibody and the second agent is a CD27 agonist antibody. 
     
     
         16 . The method or particle of any one of  claims 1 - 10 , wherein the first agent is a CD73 antagonist antibody and the second agent is a CD28 agonist antibody. 
     
     
         17 . The method or particle of any one of  claims 1 - 10 , wherein the T cell is selected from the group consisting of a CD4+ T cell and a CD8+ T cell. 
     
     
         18 . The method of any one of  claims 1 - 17 , wherein:
 (i) the tumor is selected from the group consisting of melanoma and colon cancer; or   (ii) the chronic viral infection is due to a virus selected from the group consisting of human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV).   
     
     
         19 . The method of any one of  claims 1 - 18 , wherein the subject is a human subject. 
     
     
         20 . The method of any one of  claims 1 - 19 , wherein administration of the immunoswitch nanoparticle to the subject comprises intratumoral injection. 
     
     
         21 . The method of any one of  claims 1 - 19 , wherein the immunoswitch nanoparticle is administered to the subject intratumorally. 
     
     
         22 . The method of any one of  claims 1 - 19 , wherein the immunoswitch nanoparticle is administered to the subject intravenously. 
     
     
         23 . The method of any one of  claims 1 - 23  or the particle of any one of  claims 1 - 17 , wherein the nanoparticle has a diameter ranging from about 50 nm to about 100 nm. 
     
     
         24 . The method of any one of  claims 1 - 23  or the particle of any one of  claims 1 - 17  and  23 , wherein the nanoparticle has a diameter of about 80 nm. 
     
     
         25 . The method of any one of  claims 1 - 23  or the particle of any one of  claims 1 - 17  and  23 - 24 , wherein the nanoparticle has an increased retention time in the subject relative to soluble first and second agents, or relative to separate nanoparticles comprising the first agent and the second agent. 
     
     
         26 . The method of any one of  claims 1 - 25 , wherein administration of the nanoparticle reduces or prevents tumor metastasis. 
     
     
         27 . The method of any one of  claims 1 - 25 , wherein administration of the nanoparticle inhibits the growth of tumor metastases. 
     
     
         28 . The method of  claim 26  or  27 , wherein the tumor metastasis expresses the same antigen as the tumor cell. 
     
     
         29 . The method of  claim 28 , wherein the same antigen comprises Her2/Neu, BRCA1, BRCA2, or K-Ras. 
     
     
         30 . The method of any one of  claims 1 - 29 , wherein tumor-specific CD8+ T cells activation is increased. 
     
     
         31 . A T cell produced during the method of treatment according to any one of  claims 1 - 30 . 
     
     
         32 . The method of any one of  claims 1 - 30 , wherein administration of the nanoparticle induces a local immune response. 
     
     
         33 . The method of any one of  claims 1 - 30 , wherein administration of the nanoparticle induces a systemic immune response. 
     
     
         34 . The method of any one of  claims 1 - 30 , wherein administration of the nanoparticle induces T cell memory, CD4 cell memory, or CD8 cell memory, or a combination thereof. 
     
     
         35 . The method of any one of  claims 1 - 30 , wherein administration of the nanoparticle induces T cell memory, inhibits tumor growth, prevents tumor growth, or delays tumor growth.