Anti CD30 chimeric antigen receptor and its use
In a first aspect, the present disclosure relates to genetically modified T-cells having a chimeric antigen receptor for use in adoptive cell therapy for treating CD30+cancer in a subject need thereof. In particular, the present disclosure relates to a T-cell containing a specific chimeric antigen receptor being toxic to CD30+cancer cells while being non-toxic to CD30+non-cancer cells. In a further aspect, the present disclosure relates to a specific chimeric antigen receptor and the nucleic acid molecule encoding the receptor as well vectors and cells containing the same. Finally, the present disclosure relates to the use of the chimeric antigen receptor for use in improving persistence and amplification of lymphocyte containing the same and the use of specific peptides for improving persistence and amplification of genetically modified lymphocytes expressing the same.
1. A method of adoptive cell therapy for treating CD30 + cancer in a subject in need thereof comprising the step of administering to said subject a T-cell 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-CD30 single chain antibody domain, comprising an HRS3 scFv peptide having the sequence as set forth in SEQ ID NO: 2, optionally a spacer domain, a transmembrane domain derived from CD28, and a cytoplasmatic signaling domain, wherein the cytoplasmic signaling domain is a CD28 endodomain lacking the Ick binding motif, having the sequence as encoded by SEQ ID NO: 6 and wherein said T-cell with the chimeric antigen receptor is toxic to CD30 + cancer cells, while being non-toxic to CD30 + non-cancer activated T-cells, B-cells and/or stem cells in said subject, and wherein said CD30 + cancer cells include one or more of CD30 + leukemia cells and CD30 + lymphoma cells.
2. The method for adoptive cell therapy for treating CD30 + cancer in a subject in need thereof according to claim 1 , wherein the T-cell with a chimeric antigen receptor further comprises a leader sequence located N-terminally to the anti-CD30 single chain antibody domain.
3. The method for adoptive cell therapy for treating CD30 + cancer in a subject in need thereof according to claim 1 wherein the spacer domain is an IgG1 CH2CH3 domain having the sequence as set forth in SEQ ID NO: 0.5.
4. The method of claim 1 , wherein the spacer domain is a mutated IgG 1 hinge-CH2CH3 domain having the sequence as set forth in SEQ ID NO: 10.
5. The method for adoptive cell therapy for treating CD30 + cancer in a subject in need thereof according to claim 1 wherein the cytoplasmic signaling domain is an intracellular domain selected from the group consisting of a CD3 zeta signaling domain, a Fc epsilon receptor gamma signaling chain and a costimulatory domain.
6. The method of claim 5 , wherein the intracellular domain is the CD3 zeta signaling domain having a sequence as encoded by SEQ ID NO: 7, or wherein the intracellular domain is the Fc epsilon receptor gamma signaling chain having a sequence as encoded SEQ ID NO:8.
7. A method for adoptive cell therapy for treating CD30 + cancer in a subject in need thereof, comprising the step of administering to said subject a T-cell 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-CD30 single chain antibody domain,
optionally a spacer domain,
a transmembrane domain, and
a cytoplasmatic signaling domain, wherein the cytoplasmic signaling domain is a CD28 endodomain lacking the Ick binding motif, having the sequence as encoded by SEQ ID NO: 6, and
wherein said T-cell with the chimeric antigen receptor is toxic to CD30 + cells of a cancer selected from the group consisting of Hodgkin's lymphoma, non-Hodgkin's B cell lymphoma, mycosis fungoides, Sézary lymphoma, anaplastic large cell lymphoma, acute lvmphocytic leukaemia, cutaneous lymphoma, lymphoproliferative diseases, systemic mastocytosis, teratocarcinoma, stem cell-derived malignancies, B-cell lymphoma and T-cell lymphoma, while being non-toxic to CD30 + non-cancer activated T-cells, B-cells and/or stem cells in said subject, and
wherein the chimeric antigen receptor is a polypeptide having the sequence as set forth in SEQ ID NO: 3.
8. The method for adoptive cell therapy for treating CD30 + cancer in a subject need thereof according to claim 1 wherein the CD30 + cancer is any one of Hodgkin's lymphoma, anaplastic large cell lymphoma, acute lymphocytic leukaemia, cutaneous lymphoma, mycosis fungoides, lymphoproliferative diseases, systemic mastocytosis, teratocarcinoma, stem cell derived malignancies, cancer stem cells.
9. The method for adoptive cell therapy for treating CD30 + cancer in a subject is need thereof according to claim 1 wherein the CD30 + cancer is a B-cell lymphoma or a T-cell lymphoma.
10. The method of adoptive cell therapy for treating CD30 + cancer in a subject in need thereof according to claim 1 wherein the CD30 + cancer is selected from the group consisting of Hodgkin's lymphoma, non-Hodgkin's B cell lymphoma, mycosis fungoides or Sézary lymphoma.