Compositions and methods for treating cancer with anti-CD123 immunotherapy
Chimeric antigen receptors containing CD123 antigen binding domains are disclosed. Nucleic acids, recombinant expression vectors, host cells, antigen binding fragments, and pharmaceutical compositions, relating to the chimeric antigen receptors are also disclosed. Methods of treating or preventing cancer in a subject, and methods of making chimeric antigen receptor T cells are also disclosed.
1. A method of treating a subject with a B-cell cancer or a lymphoma, the method comprising administering to the subject a pharmaceutical composition comprising an anti-tumor effective amount of a population of autologous T-cells, wherein the autologous T-cells comprise a nucleic acid sequence that encodes a chimeric antigen receptor (CAR) and is operably linked to a promoter, wherein the CAR comprises at least one extracellular antigen binding domain comprising a CD 123 antigen binding domain comprising the amino acid sequence of SEQ ID NO: 78, 88, 92, 94, 100, 102, 106, 110, or 112, at least one linker or at least one spacer domain, at least one transmembrane domain, and at least one intracellular signaling domain thereby treating the B-cell cancer or the lymphoma in the subject.
2. The method of claim 1 , wherein the at least one transmembrane domain comprises a transmembrane domain of the alpha, the beta or the zeta chain of a T-cell receptor, a CD8, a CD28, a CD3 epsilon, a CD45, a CD4, a CD5, a CD8, a CD9, a CD16, a CD22, a CD33, a CD37, a CD64, a CD80, a CD86, a CD134, a CD137, or CD154.
3. The method of claim 1 , wherein the at least one extracellular antigen binding domain comprising the CD123 antigen binding domain, the at least one intracellular signaling domain, or both are connected to the at least one transmembrane domain by the at least one linker or the at least one spacer domain.
4. The method of claim 1 , wherein the at least one linker or the at least one spacer domain is obtained from the extracellular domain of CD8, TNFRSF19, or CD28, and is linked to the at least one transmembrane domain.
5. The method of claim 1 , wherein the at least one extracellular antigen binding domain comprising the CD123 antigen binding domain is preceded by a leader nucleotide sequence encoding a leader peptide.
6. The method of claim 1 , wherein the at least one intracellular signaling domain further comprises a CD3 zeta intracellular domain.
7. The method of claim 1 , wherein the at least one intracellular signaling domain comprises a costimulatory domain, a primary signaling domain, or any combination thereof.
8. The method of claim 7 , wherein the at least one costimulatory domain comprises a functional signaling domain of OX40, CD70, CD27, CD28, CD5, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), DAP10, DAP12, or 4-1BB (CD137).
9. The method of claim 1 , wherein the B-cell cancer is a hematological B-cell cancer.
10. The method of claim 1 , wherein the B-cell cancer is chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), or acute lymphoblastic B cell leukemia (B-ALL).
11. The method of claim 1 , wherein the lymphoma is mantle cell lymphoma, non-Hodgkin's lymphoma or Hodgkin's lymphoma.