Compositions and methods for treating cancer with anti-CD19/CD22 immunotherapy
Chimeric antigen receptors containing CD19/CD22 or CD22/CD19 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 cancer in a human subject in need thereof, the method comprising administering to the human 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 CD19/CD22 tandem chimeric antigen receptor (CAR), comprising an extracellular antigen binding domain comprising a CD19/CD22 antigen binding domain, a transmembrane domain, and an intracellular signaling domain, wherein the CD19/CD22 tandem CAR comprises the amino acid sequence comprising SEQ ID NO: 2, 4, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, or 83, thereby treating the cancer of the human subject.
2. The method of claim 1 , wherein the 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 and a CD154.
3. The method of claim 1 , wherein the extracellular antigen binding domain comprising the CD19/CD22 antigen binding domain, the intracellular signaling domain, or both are connected to the transmembrane domain by a linker or a spacer domain.
4. The method of claim 3 , wherein the linker or the spacer domain is derived from the extracellular domain of CD8 or CD28, and is linked to the transmembrane domain.
5. The method of claim 1 , wherein the extracellular antigen binding domain comprising the CD19/CD22 antigen binding domain is preceded by a leader nucleotide sequence encoding a leader peptide.
6. The method of claim 1 , wherein the intracellular signaling domain comprises a costimulatory domain comprising a functional signaling domain of a protein selected from the group consisting of OX40, CD70, CD27, CD28, CD5, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), DAP10, DAP12, 4-1BB (CD137), and a combination thereof.
7. The method of claim 1 , wherein the nucleic acid sequence encoding the CD19/CD22 tandem chimeric antigen receptor (CAR) is encoded by a nucleotide sequence comprising SEQ ID NO. 1, 3, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, or 82, or a sequence with 85%, 90%, 95%, 96%, 97%, 98% or 99% identity thereof.
8. The method of claim 1 , wherein the intracellular signaling domain comprises a costimulatory domain, a primary signaling domain, or any combination thereof.
9. The method of claim 1 , wherein the intracellular signaling domain comprises a CD3 zeta intracellular domain.
10. The method of claim 1 , wherein the cancer is a hematological cancer.
11. The method of claim 10 , wherein the hematological cancer is leukemia or lymphoma.
12. The method of claim 11 , wherein the leukemia is chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), or chronic myelogenous leukemia (CML).
13. The method of claim 11 , wherein the lymphoma is mantle cell lymphoma, non-Hodgkin's lymphoma or Hodgkin's lymphoma.
14. The method of claim 1 , wherein the cancer is an adult carcinoma, selected from the group consisting of: an oral and pharynx cancer, a digestive system cancer, a respiratory system cancer, bones and joint cancers, a soft tissue cancer, a skin cancer, a cancer of the central nervous system, a breast cancer, a genital cancer, an urinary cancer, a cancer of the eye and orbit, an endocrine cancer, and a brain cancer.