Compositions and methods for treating cancer with anti-ROR1 immunotherapy
Chimeric antigen receptors containing ROR1 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. An isolated nucleic acid molecule encoding a chimeric antigen receptor (CAR) comprising at least one extracellular antigen binding domain comprising a ROR1 antigen binding domain encoded by a nucleotide sequence comprising SEQ ID NO: 1, or SEQ ID NO: 7, a transmembrane domain comprising CD8 transmembrane domain, an intracellular signaling domain comprising a functional signaling domain of 4-1BB and a CD3 zeta intracellular domain.
2. A vector comprising a nucleic acid molecule of claim 1 .
3. The vector of claim 2 , wherein the vector is selected from the group consisting of a DNA vector, an RNA vector, a plasmid vector, a cosmid vector, a herpes virus vector, a measles virus vector, a lentivirus vector, adenoviral vector, or a retrovirus vector, or a combination thereof.
4. A cell comprising the vector of claim 2 .
5. A pharmaceutical composition comprising an anti-cancer effective amount of a population of human T cells genetically modified to express on their surface a chimeric antigen receptor (CAR), wherein the T cells comprise a nucleic acid sequence that encodes the CAR, wherein the CAR comprises at least one extracellular antigen binding domain comprising a ROR1 antigen binding domain comprising the amino acid sequence of SEQ ID NO. 2, or 8, a linker domain derived from the extracellular domain of IgG4 or CD8, a transmembrane domain comprising CD8 transmembrane domain, an intracellular signaling domain comprising a functional signaling domain of 4-1BB and a CD3 zeta intracellular domain, and wherein the T cells are T cells of a human having a ROR-1 expressing cancer.
6. A method of treating a receptor tyrosine kinase-like orphan receptor 1 (ROR-1) expressing cancer in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising an anti-cancer effective amount of a population of human T cells genetically modified to express on their surface a chimeric antigen receptor (CAR), wherein the T cells comprise a nucleic acid sequence that encodes the CAR, wherein the CAR comprises at least one extracellular antigen binding domain comprising a ROR1 antigen binding domain comprising the amino acid sequence of SEQ ID NO. 2, or 8, a linker or spacer domain derived from the extracellular domain of IgG4 or CD8, a transmembrane domain comprising CD8 transmembrane domain, an intracellular signaling domain comprising a functional signaling domain of 4-1BB and a CD3 zeta intracellular domain, wherein the T cells are T cells of the subject having the ROR-1 expressing cancer.
7. The method of claim 6 , wherein the extracellular ROR1 antigen binding domain is preceded by a leader nucleotide sequence encoding a leader peptide.
8. The method of claim 6 , wherein the nucleic acid sequence encoding the extracellular ROR1 antigen binding domain comprises a nucleic sequence comprising SEQ ID NO: 1 or 7.
9. The method of claim 6 , wherein the ROR-1 expressing cancer is a hematological cancer.
10. The method of claim 9 , wherein the hematological cancer is leukemia, lymphoma, or multiple myeloma.
11. The method of claim 10 , wherein the leukemia is chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), or chronic myelogenous leukemia (CIVIL).
12. The method of claim 10 , wherein the lymphoma is mantle cell lymphoma, non-Hodgkin's lymphoma or Hodgkin's lymphoma.
13. The method of claim 6 , wherein the ROR-expressing cancer is an adult carcinoma selected from the group consisting of an oral and pharynx cancer, digestive system cancers, respiratory system cancers, bones and joint cancers, soft tissue cancers, skin cancers, pediatric tumors, tumors of the central nervous system, cancers of the breast, the genital system, the urinary system, the eye and orbit, the endocrine system, and the brain and other nervous system, or any combination thereof.