Tnfrsf14 / hvem proteins and methods of use thereof

Abstract

In some aspects the present invention provides methods for the treatment of B-cell lymphomas. Some such methods involve administration of HVEM ectodomain polypeptides, anti-HVEM antibodies, or anti-BTLA antibodies to subjects in need thereof. Some such methods involve use of CAR T cells, such as CD19-specific CAR T cells. The present invention also provides compositions useful in such methods. These and other embodiments of the present invention and described further herein.

1 - 195 . (canceled) 
     
     
         196 . A method of treating B-cell lymphoma in a subject in need thereof, the method comprising administering an effective amount of a soluble HVEM ectodomain polypeptide to a subject with a BTLA+ B cell lymphoma, wherein the soluble HVEM ectodomain polypeptide comprises a HVEM CRD1 domain, a HVEM CRD2 domain, and a HVEM CRD3 domain, thereby treating the B-cell lymphoma in the subject. 
     
     
         197 . The method of  claim 196 , wherein the B-cell lymphoma cell is follicular lymphoma or diffuse large B-cell lymphoma. 
     
     
         198 . The method of  claim 196 , wherein the B-cell lymphoma cell is follicular lymphoma. 
     
     
         199 . The method of  claim 196 , wherein the soluble HVEM ectodomain polypeptide comprises amino acids 42-162 of SEQ ID NO. 2. 
     
     
         200 . The method of  claim 196 , wherein the soluble HVEM ectodomain polypeptide comprises SEQ ID NO: 4, 6, or 8. 
     
     
         201 . The method of  claim 196 , wherein the soluble HVEM ectodomain polypeptide is encoded by a nucleotide sequence comprising SEQ ID NO. 3, 5, or 7. 
     
     
         202 . The method of  claim 196 , wherein the soluble HVEM ectodomain polypeptide is administered by administering to the subject genetically modified T cells that comprise:
 (a) a nucleotide sequence encoding a chimeric antigen receptor (CAR), wherein the CAR binds to a cell surface antigen on a B-cell lymphoma cell, and   (b) a nucleotide sequence encoding the soluble HVEM ectodomain polypeptide.   
     
     
         203 . The method of  claim 202 , wherein the wherein the CAR binds to a cell surface antigen selected from the group consisting of CD19, CD20, CD22, CD30, Igk and ROR1. 
     
     
         204 . The method of  claim 203 , wherein the CAR binds to CD19. 
     
     
         205 . The method of  claim 204 , wherein the CAR comprises the complementarity determining regions of the anti-CD19 CAR encoded by SEQ ID NO. 9. 
     
     
         206 . The method of  claim 196 , wherein the soluble HVEM ectodomain polypeptide is administered in a composition that comprises an antibody, or antigen-binding domain of an antibody, that binds to a cell surface antigen on a B-cell lymphoma cell. 
     
     
         207 . The method of  claim 206 , wherein the cell surface antigen is selected from the group consisting of CD19, CD20, CD22, CD30, Igk and ROR1. 
     
     
         208 . The method of  claim 207 , wherein the cell surface antigen is CD20. 
     
     
         209 . The method of  claim 206 , wherein the composition comprises a fusion protein, wherein the fusion protein comprises the soluble HVEM ectodomain polypeptide and the antibody or antigen-binding domain. 
     
     
         210 . The method of  claim 209 , wherein the antibody or antigen-binding domain binds to a cell surface antigen selected from the group consisting of CD19, CD20, CD22, CD30, Igk and ROR1. 
     
     
         211 . The method of  claim 210 , wherein the cell surface antigen is CD20.