Use of Triplex CMV Vaccine in CAR T Cell Therapy

Abstract

A method for treating a patient comprising: (a) providing a composition comprising a population of T cells expressing both a chimeric antigen receptor (CAR) and a T cell receptor specific for a cytomegalovirus (CMV) antigen; (b) administering the composition to the patient; and (c) administering to the patient a viral vector encoding: (i) CMV pp65 and (ii) a fusion protein comprising exon 4 of CMV protein IE1 (e4) and exon 5 of CMV protein 1E2 (e5) either prior to or subsequent to administering the composition comprising a population of T cells to the patient is described.

1 - 50 . (canceled) 
     
     
         51 . A method for treating a patient comprising:
 (a) providing a composition comprising a population of T cells expressing both a chimeric antigen receptor (CAR) and a T cell receptor specific for a cytomegalovirus (CMV) antigen;   (b) administering the composition of part (a) to the patient; and   (c) administering to the patient a viral vector encoding:
 (i) CMV pp65 and 
 (ii) a fusion protein comprising exon 4 of CMV protein IE1 (e4) and exon 5 of CMV protein IE2 (e5). 
   
     
     
         52 . The method of  claim 51 , wherein the viral vector of part (a) is a MVA virus. 
     
     
         53 . The method of  claim 52 , wherein expression of (i) CMV pp65 and (ii) the fusion protein comprising exon 4 of CMV protein IE1 (e4) and exon 5 of CMV protein IE2 (e5) is under the control of mH5 promoter. 
     
     
         54 . The method of  claim 51 , wherein the patient is CMV-seronegative prior to treatment. 
     
     
         55 . The method of  claim 51 , wherein the patient is CMV-seropositive prior to treatment. 
     
     
         56 . The method of  claim 51 , wherein the CAR is targeted to CD19. 
     
     
         57 . The method of  claim 51 , wherein the viral vector is administered to the patient both prior to and subsequent to the administration of the composition comprising a population of T cells. 
     
     
         58 . The method of  claim 51 , wherein the step of providing a population of T cells expressing a CAR and a T cell receptor specific for a CMV antigen comprises:
 (a1) providing PBMC or a T cell subpopulation from a CMV-seropositive human donor;   (a2) exposing the PBMC or the T cell subpopulation of part (a1) to at least one CMV antigen;   (a3) treating the exposed cells of part (a2) to produce a population of cells enriched for cells specific for CMV; and   (a4) transducing at least a portion of the enriched population of cells of part (a3) with a vector expressing a CAR.   
     
     
         59 . The method of  claim 58 , wherein the step of treating the exposed cells to produce a population of cells enriched for cells specific for CMV comprises treating the cells to produce a population of cells enriched for cells expressing an activation marker. 
     
     
         60 . The method of  claim 51 , wherein the step of providing a population of T cell expressing a CAR and a T cell receptor specific for a CMV antigen further comprises:
 (a1) administering a viral vector encoding: (i) CMV pp65 and (ii) a fusion protein comprising exon 4 of CMV protein IE1 (e4) and exon 5 of CMV protein IE2 (e5) to a human donor to convert a CMV-seronegative human donor to one containing T cells responsive to CMV antigens pp65, IE1 and IE2;   (a2) obtaining PBMC from the CMV-seropositive human donor of (a1);   (a3) exposing the PBMC of (a2) to at least one CMV antigen;   (a4) treating the exposed cells of (a3) to produce a population of cells enriched for stimulated cells specific for CMV; and   (a5) transducing at least a portion of the enriched population of cells of (a4) with a vector expressing a CAR, thereby providing a population of T cell expressing a CAR and a T cell receptor specific for a CMV antigen.   
     
     
         61 . The method of  claim 51 , wherein the step of providing a population of T cell expressing a CAR and a T cell receptor specific for a CMV antigen comprises:
 (a1) administering a viral vector encoding: (i) CMV pp65 and (ii) a fusion protein comprising exon 4 of CMV protein IE1 (e4) and exon 5 of CMV protein IE2 (e5) to a CMV-positive human donor;   (a2) obtaining PBMC from the CMV-seropositive human donor of (a1);   (a3) exposing the PBMC of (a2) to at least one CMV antigen;   (a4) treating the exposed cells of (a3) to produce a population of cells enriched for stimulated cells specific for CMV;   (a5) transducing at least a portion of the enriched population of cells of (a4) with a vector expressing a CAR, thereby providing a population of T cell expressing a CAR and a T cell receptor specific for a CMV antigen.   
     
     
         62 . A method for preparing T cells expressing a CAR and a T cell receptor specific for a CMV antigen, the method comprising:
 (a) administering a viral vector encoding: (i) CMV pp65 and (ii) a fusion protein comprising exon 4 of CMV protein IE1 (e4) and exon 5 of CMV protein IE2 (e5) to a CMV-positive human donor;   (b) obtaining PBMC from the CMV-seropositive human donor;   (c) exposing the PBMC to at least one CMV antigen;   (d) treating the exposed cells to produce a population of cells enriched for stimulated cells specific for CMV; and   (e) transducing at least a portion of the enriched population of cells with a vector expressing a CAR, thereby providing a population of T cell expressing a CAR and a T cell receptor specific for a CMV antigen.   
     
     
         63 . A method for preparing T cells expressing a CAR and a T cell receptor specific for a CMV antigen, the method comprising:
 (a) administering a viral vector encoding: (i) CMV pp65 and (ii) a fusion protein comprising exon 4 of CMV protein IE1 (e4) and exon 5 of CMV protein IE2 (e5) to a CMV-positive human donor;   (b) obtaining PBMC from the CMV-seropositive human donor;   (c) (b) exposing the PBMC to at least one CMV antigen;   (d) treating the exposed cells to produce a population of cells enriched for stimulated cells specific for CMV; and   (e) transducing at least a portion of the enriched population of cells with a vector expressing a CAR, thereby providing a population of T cell expressing a CAR and a T cell receptor specific for a CMV antigen.   
     
     
         64 . The method of  claim 51 , wherein the CAR is selective for an antigen selected from: CD19, CD123, CS1, BCMA, CD44v6, CD33, CD22, IL-13α2, PSA, HER-2, EGFRv3, CEA, and C7R. 
     
     
         65 . The method of  claim 51 , wherein the CAR comprises: a scFv selective for a non-CMV antigen; a hinge/linker region; a transmembrane domain; a co-signaling domain; and
 CD3 ζ signaling domain.   
     
     
         66 . The method of  claim 65 , wherein the co-signaling domain is selected from a CD28 co-signaling domain and a 4-IBB co-signaling domain. 
     
     
         67 . The method of  claim 65 , wherein the transmembrane domain is selected from a CD28 transmembrane domain and a CD4 transmembrane