Hepatic arterial infusion of car-t cells

Abstract

Disclosed herein are compositions and methods for the treatment of liver metastases in a subject. The methods include hepatic arterial infusion (HAI) of chimeric antigen receptor modified T cells (CAR-T) which are highly specific for tumor antigens such as carcinoembryonic antigen (CEA). The HAI method is optimized to maximize exposure of the modified cells to the metastatic cells while minimizing exposure to healthy cells. The methods include co-administration of a second therapeutic agent, such as IL-2.

What is claimed is: 
     
         1 . A method for treating a liver metastasis in a subject, comprising:
 infusing into the hepatic artery of the subject a composition comprising a chimeric antigen receptor T cell (CAR-T cell) which expresses a chimeric antigen receptor protein, wherein the chimeric antigen receptor protein binds to an antigen expressed on metastatic cells in the liver.   
     
     
         2 . The method according to  claim 1 , further comprising performing angiography to mapthe hepatic artery and nearby vessels prior to the infusing step. 
     
     
         3 . The method according to  claim 2 , further comprising occluding vessels which do not feed into the liver. 
     
     
         4 . The method according to  claim 1 , further comprising performing angiography during the infusing step, wherein the angiography monitors intrahepatic hemodynamic integrity during the infusing step. 
     
     
         5 . The method according to any one of the preceding claims, wherein the chimeric antigen receptor protein specifically binds carcinoembryonic antigen (CEA) expressed on the surface of the metastatic cells. 
     
     
         6 . The method according to  claim 1 , wherein the chimeric antigen receptor protein comprises SEQ ID NO: 1. 
     
     
         7 . The method according to  claim 1 , further comprising administering a second therapeutic agent into the hepatic artery of the subject. 
     
     
         8 . The method according to  claim 7 , wherein the second therapeutic agent is IL-2. 
     
     
         9 . The method according to  claim 8 , wherein the administering the second therapeutic agentis performed before, during or after the infusion of the composition comprising the immunoresponsive cell. 
     
     
         10 . The method according to  claim 1 , wherein the composition comprising the CAR-T cells is infused into the hepatic artery of the subject once every 1 week, once every 2 weeks, once every 3 weeks, or once every 4 weeks. 
     
     
         11 . The method according to  claim 1 , wherein the infusion into the hepatic artery of the subject the composition comprising the CAR-T cells comprises infusing 10 8  to 10 10  CAR-T cells into the hepatic artery. 
     
     
         12 . The method according to  claim 1 , wherein the infusion the composition results in a 40% to 50% decrease in serum CEA as compared to the level of CEA in the serum prior to the infusion. 
     
     
         13 . A method for treating a liver metastasis in a subject, comprising:
 infusing into the hepatic artery of the subject a composition comprising a CAR-T cell which expresses a chimeric antigen receptor protein (CAR), wherein the CAR protein binds to CEA.   
     
     
         14 . The method according to  claim 13 , wherein the chimeric antigen receptor protein comprises SEQ ID NO:1. 
     
     
         15 . The method according to  claim 14 , wherein the CAR comprises in an N-terminal to C-terminal direction: an scFv which binds CEA, a CD8 hinge domain, a CD28 extracellular domain, a CD28 transmembrane domain, a CD28 cytoplasmic domain, and a CD3 zeta cytoplasmic domain. 
     
     
         16 . The method according to  claim 15 , wherein the infusing comprises infusing 10 8  to 10 10  CAR-T cells into the hepatic artery. 
     
     
         17 . The method according to  claim 15 , further comprising administering a composition comprising a second therapeutic agent to the subject. 
     
     
         18 . The method according to  claim 17 , wherein the second therapeutic agent is IL-2 oryttrium-90. 
     
     
         19 . A method for decreasing CEA in the serum of a subject diagnosed with liver metastases, wherein the method comprises infusing into the hepatic artery of the subject a composition comprising a chimeric antigen receptor T cell (CAR-T cell) which expresses a chimeric antigen receptor protein, wherein the chimeric antigen receptor protein binds to an antigen expressed on metastatic cells in the liver. 
     
     
         20 . The method according to  claim 19 , wherein the chimeric antigen receptor protein binds CEA.