Anti-TOSO chimeric antigen receptor and its use
In a first aspect, the present invention relates to genetically modified T-cells having a chimeric antigen receptor (CAR) in a method for adoptive cell therapy for treating TOSO + cancer, like B-cell leukemia/lymphoma, in a subject in need thereof. In particular, the present invention relates to a genetically engineered T-cell containing and expressing a specific chimeric antigen receptor being toxic to TOSO + cancer cells while being less toxic or non-toxic to TOSO + non-cancer cells, in particular, being non-toxic to normal B cells and its precursors. In a further aspect, the present invention relates to a specific chimeric antigen receptor and the nucleic acid molecule encoding the same as well as vectors and cells containing the same.
1. A method for treating TOSO + cancer in a subject in need thereof by adoptive cell therapy including the step of administering T-cells with a chimeric antigen receptor whereby the chimeric antigen receptor contains at least the following domains starting from the N-terminus to the C-terminus: an anti-TOSO single chain antibody domain; a transmembrane domain; and a cytoplasmic signaling domain; optionally a spacer domain between the anti-TOSO single chain antibody domain and the transmembrane domain, whereby the T-cells with the chimeric antigen receptor initiates or augments the immune response to or is toxic to TOSO + cancer cells while being less or non-toxic to TOSO+ non-cancer cells in said subject, wherein the transmembrane domain is derived from a human CD28, and wherein the cytoplasmic signaling domain contains at least one domain selected from the group consisting of a human CD3 zeta signaling domain, a human Fc epsilon receptor gamma-signaling domain, and a human CD28 signaling domain lacking the lck binding motif.
2. The method for treating TOSO + cancer in a subject in need thereof by adoptive cell therapy according to claim 1 , wherein the TOSO + cancer is TOSO + leukemia or TOSO + lymphoma.
3. The method for treating TOSO + cancer in a subject in need thereof by adoptive cell therapy according to claim 1 , wherein the anti-TOSO single chain antibody domain is the 6B10 scFv peptide as set forth in SEQ ID NO: 2.
4. The method for treating TOSO + cancer in a subject in need thereof by adoptive cell therapy according to claim 1 , further comprising a leader sequence being located N-terminally to the anti-TOSO single chain antibody domain.
5. The method for treating TOSO + cancer in a subject in need thereof by adoptive cell therapy according to claim 1 , wherein the spacer domain is a mutated IgG 1 CH2CH3 domain as set forth in SEQ ID NO: 5.
6. The method for treating TOSO+ cancer in a subject in need thereof by adoptive cell therapy according to claim 1 , wherein the cytoplasmic signaling domain contains at least one domain selected from the group consisting of the human CD3 zeta signaling domain having the sequence as set forth in SEQ ID NO: 7, and the human Fc epsilon receptor gamma-signaling domain having the sequence as set forth in SEQ ID NO: 8.
7. The method for treating TOSO+ cancer in a subject in need thereof by adoptive cell therapy according to claim 1 , wherein the cytoplasmic signaling domain is the human CD28 signaling domain lacking the Ick binding motif having the sequence as set forth in SEQ ID NO: 6.
8. The method for treating TOSO + cancer in a subject in need thereof by adoptive cell therapy according to claim 1 , wherein the chimeric antigen receptor is the polypeptide as set forth in SEQ ID NO: 4.
9. The method for treating TOSO + cancer in a subject in need thereof by adoptive cell therapy according to claim 1 , wherein the TOSO + cancer is any one of leukemia or lymphoma, in particular chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, anaplastic large cell lymphoma, acute lymphocytic leukemia, cutaneous lymphoma, or stem cell-derived malignancies or cancer stem cells.
10. The method of claim 6 , wherein the cytoplasmic signaling domain further comprises a costimulatory domain.