TREATMENT OF TRBC1-POSITIVE T CELL MALIGNANCIES
The present disclosure relates to the treatment of T Cell Receptor Beta Constant 1 (TRBC1)-positive T-cell malignancies with CAR T cells targeting TRBC1.
1 . A method for treating a TRBC1-positive malignancy in a patient comprising administering to the patient autologous anti-TRBC1 CAR T-cells.
2 . The method of claim 1 wherein the age of the patient is eighteen years or older.
3 . The method of claim 1 or 2 wherein the TRBC1-positive malignancy is: peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), angio-immunoblastic T-cell lymphoma (AITL), or anaplastic large cell lymphoma (ALCL).
4 . The method of claim 1 or 2 wherein the TRBC1-positive malignancy is 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.
5 . The method of any preceding claim wherein the patient has:
a) relapsed or refractory T-cell malignancy following at least one line of therapy, and
b) confirmed TRBC1-positive tumour.
6 . The method of any preceding claim wherein the patient is administered a single dose of about 25×10 6 , 75×10 6 , 225×10 6 , 450×10 6 , or 900×10 6 anti-TRBC1 CAR T cells.
7 . The method of claim 6 wherein the patient is administered a single dose of 450×10 6 anti-TRBC1 CAR T cells.
8 . The method of any preceding claim wherein the administration is an intravenous injection through a Hickman line or peripherally inserted central catheter.
9 . The method of any preceding claim wherein the patient receives a pre-conditioning chemotherapy.
10 . The method of claim 1 wherein the anti-TRBC1 CAR T-cells express a CAR comprising a TRBC1-binding domain which comprises
a) a heavy chain variable region (VH) having
CDRs with the following sequences:
VH CDR1:
(SEQ ID NO: 1)
GYTFTGY,
VH CDR2:
(SEQ ID NO: 2)
NPYNDD
and
VH CDR3:
(SEQ ID NO: 3)
GAGYNFDGAYRFFDF;
and
b) a light chain variable region (VL) having
CDRs with the following sequences:
VL CDR1:
(SEQ ID NO: 4)
RSSQRLVHSNGNTYLH,
VL CDR2:
(SEQ ID NO: 5)
RVSNRFP
and
VL CDR3:
(SEQ ID NO: 6)
SQSTHVPYT.
11 . The method of claim 10 , wherein the anti-TRBC1 binding domain comprises a VH domain having the sequence shown as SEQ ID NO: 9, or a variant thereof with at least 95% sequence identity.
12 . The method of claim 10 , wherein the anti-TRBC1 binding domain comprises a VL domain having the sequence shown as SEQ ID NO: 19, or a variant thereof with at least 95% sequence identity.
13 . The method of claim 10 , wherein the anti-TRBC1 binding domain comprises a VH domain having the sequence shown as SEQ ID NO: 9 and a VL domain having the sequence shown as SEQ ID NO: 19, or a variant thereof with at least 95% sequence identity.
14 . The method of claim 10 , wherein the anti-TRBC1 domain comprises the six CDRs grafted on to a human antibody framework.
15 . The method of any preceding claim , wherein the CAR comprises the anti-TRBC1 binding domain and a transmembrane domain connected by a spacer.
16 . The method of claim 15 , wherein the spacer comprises a human IgG1 hinge.
17 . The method of any preceding claim wherein the CAR comprises an intracellular T cell signaling domain comprising a 41BB endodomain and a CD3-Zeta endodomain.
18 . The method of claim 10 wherein the CAR comprises an anti-TRBC1 binding domain comprises a VH domain having the sequence shown as SEQ ID NO: 9 and a VL domain having the sequence shown as SEQ ID NO: 19, a human IgG1 hinge, and an intracellular T cell signaling domain comprising a 41 BB endodomain and a CD3-Zeta endodomain.
19 . The method of claim 10 wherein the CAR comprises the sequence shown in SEQ ID NO: 35.