Methods of depleting malignant T-cells
The present invention relates to a chimeric antigen receptor (CAR) which comprises an antigen-binding domain which selectively binds TCR beta constant region 1 (TRBC1) or TRBC2; cells; such a T cells comprising such a CAR; and the use of such cells for the treatment of a T-cell lymphoma or leukaemia in a subject.
1. A method of depleting malignant T-cells in a human subject with a T-cell lymphoma or leukaemia, the method comprising:
determining the percentage of total T-cells in a sample from the subject which is TRBC1 positive and determining the percentage of total T-cells in the sample which is TRBC2 positive,
detecting a percentage of TRBC1 positive T-cells that is greater than 80% or detecting a percentage of TRBC2 positive T-cells that is greater than 80%,
diagnosing the subject as having a T-cell lymphoma or leukaemia from the percentage that is greater than 80%, and
selectively depleting T-cells in the subject determined to have the T cell lymphoma or leukaemia by
(a) administering an agent that selectively binds to and depletes malignant and normal T-cells that are TRBC1-positive, if the subject is determined to have a percentage of TRBC1-positive T-cells which is greater than 80%, or
(b) administering an agent that selectively binds to and depletes malignant and normal T cells that are TRBC2-positive, if the subject is determined to have a percentage of TRBC2-positive T-cells which is greater than 80%,
wherein the agent of (a) is an engineered T-cell expressing a chimeric antigen receptor (CAR) which selectively binds TRBC1 and comprises a spacer comprising an IgG1 hinge or a CD8 stalk, and
wherein the agent of (b) is an engineered T-cell expressing a CAR which selectively binds TRBC2 and comprises a spacer comprising an IgG1 hinge or a CD8 stalk.
2. The method of cairn 1 wherein the sample is a peripheral blood sample or a biopsy.
3. The method of claim 1 wherein the CAR comprises an endodomain comprising a co-stimulatory component and a CD3-Zeta component.
4. The method of claim 1 wherein the IgG1 hinge is an IgG1 hinge altered to remove Fc binding motifs.
5. A method of selectively depleting malignant T-cells without depleting the entire T-cell compartment in a human subject, the method comprising:
(a) determining whether a malignant T cell in a sample containing T cells from the subject expresses TRBC1 or TRBC2, and
(b) when the malignant T cell expresses TRBC1, selectively depleting malignant and normal T-cells in the subject that express TRBC1 by administering to the subject an agent that selectively binds to TRBC1 and that depletes said malignant and normal T-cells, wherein the agent is an engineered T-cell expressing a chimeric antigen receptor (CAR) that selectively binds to TRBC1 and that comprises a spacer comprising an IgG1 hinge or CD8 stalk; or,
when the malignant T cell expresses TRBC2, selectively depleting malignant and normal T-cells in the subiect that express TRBC2 by administering to the subject an agent that selectively binds to TRBC2 and that depletes said malignant and normal T-cells, wherein the agent is an engineered T-cell expressing a CAR that selectively binds to TRBC2 and that comprises a spacer comprising an IgG1 hinge or CD8 stalk.
6. The method of claim 5 wherein the malignant T-cells in the subject are T-cell lymphoma or leukaemia cells.
7. The method of claim 6 wherein the malignant T-cells are from a peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS); angio-immunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma (ALCL), enteropathy-associated T-cell lymphoma (EATL), hepatosplenic T-cell lymphoma (HSTL), extranodal NK/T-cell lymphoma nasal type, cutaneous T-cell lymphoma, primary cutaneous ALCL, T cell prolymphocytic leukaemia and T-cell acute lymphoblastic leukaemia.
8. The method of claim 5 wherein the CAR comprises an endodomain comprising a co-stimulatory component and a CD3-Zeta component.
9. The method of claim 5 wherein the IgG1 hinge is an IgG1 hinge altered to remove Fc binding motifs.