Use of endogenous viral vaccine in chimeric antigen receptor T cell therapy
Inventors
Williams, John C. • Brown, Christine • Diamond, Don J. • Wang, Xiuli • Forman, Stephen J.
Assignees
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Publication Number
US-12161714-B2
Publication Date
2024-12-10
Expiration Date
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 vivo 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.
Core Innovation
The disclosed subject matter provides a cell comprising a T cell receptor specific for a cytomegalovirus (CMV) antigen and a recombinant CAR protein. The CAR protein comprises an antibody region and a transmembrane domain, and the antibody region includes 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).
Within the antibody region, the central cavity forms a peptide binding site comprising framework region amino acid residues. The CMV context includes pp65 antigenic proteins, including antigenic portions, and the disclosure characterizes the CAR as a meditope-enabled CAR architecture using the antibody region central cavity for peptide binding.
The document additionally describes pairing the CAR T cells with administration of a CMV-based viral vector/vaccine expressing CMV pp65 and an IE1/IE2 exon fusion, including recombinant MVA virus and a promoter controlling pp65 and the IE fusion. The viral vector is given before and/or after CAR T administration to promote in vivo expansion and re-stimulation, and the disclosed embodiments further include refinements to CAR intracellular signaling and co-stimulation domains and alternative anti-antigen CAR target options.
Claims Coverage
The claim set centers on a cell combining a CMV-antigen-specific TCR with a recombinant CAR. Two core inventive features define the CAR: a framework-residue central peptide-binding cavity in the antibody region and a transmembrane domain. Dependent claims refine the CMV antigen, add intracellular signaling and co-stimulatory domains, and list broad alternative anti-antigen specificities.
CMV-specific T cell receptor and recombinant CAR in a single cell
A cell comprising a T cell receptor specific for a cytomegalovirus (CMV) antigen and a recombinant CAR protein.
Central cavity peptide binding antibody region from VH/VL/CH/CL with framework residues
The recombinant CAR protein comprises 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 the central cavity forms a peptide binding site comprising framework region amino acid residues.
Transmembrane domain for the recombinant CAR protein
The recombinant CAR protein comprises a transmembrane domain.
CMV antigen as pp65 protein or antigenic portion
The cell wherein the CMV antigen is either the pp65 protein or an antigenic portion of the pp65 protein.
CMV antigen comprising two or more different antigenic pp65 proteins
The cell wherein the CMV antigen is made up of two or more different antigenic pp65 proteins.
Intracellular T-cell signaling domain
The cell wherein the recombinant CAR protein further includes an intracellular T-cell signaling domain.
Intracellular co-stimulatory signaling domain
The cell wherein the recombinant CAR protein additionally includes an intracellular co-stimulatory signaling domain.
Recombinant CAR as one of multiple listed anti-antigen specificities
The cell wherein the recombinant CAR protein is an anti-CD19, anti-CD20, anti-CD22, anti-CD30, anti-CD33, anti-CD44v6/7/8, anti-CD123, anti-CEA, anti-EGP-2, anti-EGP-40, anti-erb-B2, anti-erb-B2,3,4, anti-FBP, anti-fetal acetylcholine receptor, anti-GD2, anti-GD3, anti-Her2/neu, anti-IL-13R-a2, anti-KDR, anti k-light chain, anti-LeY, anti-L1 cell adhesion molecule, anti-MAGE-A1, anti-mesothelin, anti-murine CMV infected cell, anti-MUC2, anti-NKGD2, anti oncofetal antigen, anti-PCSA, anti-PSMA, anti-TAA, anti-EGFR, antiTAG-72, or anti-VEGF-72 protein.
Across the claim set, coverage centers on a cell combining a CMV-antigen-specific TCR with a recombinant CAR whose antibody region forms a framework-residue central cavity peptide binding site and includes a transmembrane domain. Dependent claims further narrow the CMV antigen to pp65, including antigenic portions and multiple different antigenic pp65 proteins, optionally add an intracellular T-cell signaling domain and an intracellular co-stimulatory signaling domain, and list broad alternative anti-antigen specificities for the recombinant CAR.
Stated Advantages
To promote in vivo expansion and re-stimulation.
To avoid or reduce exhaustion from ex vivo manufacture.
Documented Applications
Use of a CMV-based viral vector/vaccine expressing CMV pp65 and an IE1/IE2 exon fusion in relation to CAR T administration to promote in vivo expansion and re-stimulation.
CAR T-cell context including CMV pp65 together with CMV-seronegative versus CMV-seropositive donor/recipient scenarios.
Anti-cancer targeting embodiments using the recombinant CAR for a broad list of listed anti-antigen targets.
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