Use of endogenous viral vaccine in chimeric antigen receptor T cell therapy

Patent metadata

Field	Value
Publication number	US-11116834-B2
Application number	US-201716342426-A
Country	US
Kind code	B2
Filing date	Oct 19, 2017
Priority date	Oct 19, 2016
Publication date	Sep 14, 2021
Grant date	Sep 14, 2021

Abstract

Provided herein are, inter alia, methods and compositions including T cells expressing (i) a recombinant CAR protein which includes a peptide binding site and is capable of specifically binding cancer-specific antigens and (ii) a T cell receptor specific for a viral antigen (e.g., a CMV pp65 protein). The engineered T cells provided herein may be used in combination with a viral vaccine (e.g. cytomegalovirus (CMV) Triplex Vaccine) to treat a variety of cancers. The methods described herein also permit in viva expansion of CMV-specific CAR T cells, instead of or in addition to ex vivo expansion, avoiding excessive T cell exhaustion that results in some cases from ex vivo manufacturing.

First claim

What is claimed is:

1. A method for treating a disease in a subject in need thereof, said method comprising:
(i) administering to a subject a therapeutically effective amount of a composition comprising a population of human T cells expressing a T cell receptor specific for a cytomegalovirus (CMV) antigen and a recombinant chimeric antigen receptor (CAR) protein, wherein said recombinant CAR protein comprises:
(A) an antibody region comprising a central cavity formed by a heavy chain variable (VH) region, a light chain variable (VL) region, a heavy chain constant region (CH) and a light chain constant region (CL), wherein said central cavity forms a peptide binding site comprising framework region amino acid residues; and
(B) a transmembrane domain; and
(ii) administering to said subject a therapeutically effective amount of a viral vector, wherein said viral vector encodes (a) a CMV pp65 protein and (b) a fusion protein comprising exon 4 of CMV protein 1E1 (e4) and exon 5 of CMV protein 1E2 (e5); and
wherein said viral vector is administered either prior to or subsequent to administering said composition comprising a population of human T cells to said subject, thereby treating said subject.

2. The method of claim 1 , wherein said step of administering a therapeutically effective amount of a viral vector to said subject comprises administering recombinant MVA virus.

3. The method of claim 1 , wherein said subject is immunocompromised.

4. The method of claim 1 , wherein said subject is immunocompetent.

5. The method of claim 1 , wherein said subject is CMV-seronegative prior to treatment.

6. The method of claim 1 , wherein said subject received hematopoietic stem cells (HSCs) from a CMV-positive or a CMV-negative donor prior to administering said a therapeutically effective amount of said composition comprising a population of human T cells expressing a T cell receptor specific for a CMV antigen and a recombinant CAR protein.

7. The method of claim 1 , wherein said subject is suffering from cancer.

8. The method of claim 1 , wherein said population of human T cells expressing a T cell receptor specific for a CMV antigen and a recombinant CAR protein is formed by: (1) isolating PBMCs or a T cell subpopulation from a CMV-seropositive human donor; (2) contacting said PBMCs or said T cell subpopulation with at least one CMV antigen; (3) allowing said contacted cells to produce a population of cells enriched for stimulated cells specific for CMV; (4) transducing at least a portion of said enriched population of cells with a vector expressing a recombinant CAR protein, thereby forming a population of human T cells expressing a T cell receptor specific for a CMV antigen and a recombinant CAR protein.

9. The method of claim 1 , wherein said population of human T cells expressing a T cell receptor specific for a CMV antigen and a recombinant CAR protein is formed by: (1) administering a viral vector encoding: (a) a CMV pp65 protein and (b) 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 a CMV-seropositive human donor containing T cells responsive to CMV antigens pp65, IE1 and IE2; (2) obtaining PBMCs from said CMV-seropositive human donor; (3) contacting said PBMCs with at least one CMV antigen; (4) allowing said contacted cells to produce a population of cells enriched for stimulated cells specific for CMV; (5) transducing at least a portion of said enriched population of cells with a vector expressing a recombinant CAR protein, thereby forming a population of T cell expressing a T cell receptor specific for a CMV antigen and a recombinant CAR protein.

10. The method of claim 1 , wherein said population of human T cells expressing a T cell receptor specific for a CMV antigen and a recombinant CAR protein is formed by: (1) administering a viral vector encoding: (a) a CMV pp65 protein and (b) a fusion protein comprising exon 4 of CMV protein IE1 (e4) and exon 5 of CMV protein IE2 (e5) to a CMV-seropositive human donor; (2) allowing PBMCs from said CMV-seropositive human donor; (3) contacting said PBMCs with at least one CMV antigen; (4) allowing said contacted cells to produce a population of cells enriched for stimulated cells specific for CMV; (5) transducing at least a portion of said enriched population of cells with a vector expressing a recombinant CAR protein, thereby providing a population of human T cells expressing a T cell receptor specific for a CMV antigen and a recombinant CAR protein.

11. A method for treating a disease in a subject in need thereof comprising:
(i) administering to a subject a therapeutically effective amount of a composition comprising a population of human T cells expressing a T cell receptor specific for a viral antigen and a recombinant chimeric antigen receptor (CAR) protein, wherein said recombinant CAR protein comprises:
(A) an antibody region comprising a central cavity formed by a heavy chain variable (VH) region, a light chain variable (VL) region, a heavy chain constant region (CH) and a light chain constant region (CL), wherein said central cavity forms a peptide binding site comprising framework region amino acid residues; and
(B) a transmembrane domain; and

(ii) administering to said subject said viral antigen either prior to or subsequent to administering said composition comprising a population of human T cells to said subject.

Assignees

• Hope City

Inventors

• Williams John C
• Brown Christine
• Diamond Don J

Classifications

• A61K40/4211

  CD19 or B4 · CPC title

• A61K40/4205

  Her-2/neu/ErbB2, Her-3/ErbB3 or Her 4/ ErbB4 · CPC title

• A61K40/4204

  Epidermal growth factor receptors [EGFR] · CPC title

• A61K40/46

  Viral antigens · CPC title

• A61K40/31

  Chimeric antigen receptors [CAR] · CPC title