Antigen specific CD19-targeted CAR-T cells
Disclosed are compositions and methods for targeted treatment of cancer, such as hematologic cancer. In particular, chimeric antigen receptor (CAR) T cells are disclosed that can be used with adoptive cell transfer to target and kill cancer cells with reduced antigen escape. Therefore, also disclosed are methods of providing an anti-tumor immunity in a subject with hematologic cancer that involves adoptive transfer of the disclosed CAR T cells.
1 . An immune cell expressing a chimeric antigen receptor (CAR) polypeptide comprising a CD19-binding domain comprising the amino acid sequence set forth in SEQ ID NO:9, a hinge region comprising the amino acid sequence set forth in SEQ ID NO:12, a transmembrane domain comprising the amino acid sequence set forth in SEQ ID NO:13, an intracellular domain comprising the amino acid sequence set forth in SEQ ID NO: 14, and an intracellular signaling domain comprising the amino acid sequence set forth in SEQ ID NO: 11;
wherein the immune cell is an EBV-antigen sensitized cytotoxic T lymphocyte (CTL); and
wherein the CAR-expressing immune cell is not derived from the subject to whom the cell is to be administered.
2 . A method of treating a B-lymphocyte antigen-associated cancer in a subject, the method comprising administering to the subject an effective amount of an adoptive immunotherapy composition comprising the CAR-expressing immune cell of claim 1 .
3 . The method of claim 2 , wherein the B-lymphocyte antigen-associated cancer is an EBV-associated lymphoproliferative disease.
4 . The immune cell of claim 1 , wherein the CAR polypeptide comprises at least one co-stimulatory signaling region, wherein the co-stimulatory signaling region comprises a signaling domain of any one of the polypeptides CD8, CD3ζ, CD3δ, CD3γ, CD3ε, FcγRI-γ, FcγRIII-γ, FcεRIβ, FcεRIγ, DAP10, DAP12, CD32, CD79a, CD79b, CD28, CD3C, CD4, b2c, CD137 (41BB), ICOS, CD27, CD288, CD80, NKp30, OX40, mutants thereof, or any combination thereof.
5 . The immune cell of claim 1 , wherein the CAR polypeptide comprises a signal peptide comprising the amino acid sequence set forth in SEQ ID NO:8.
6 . The immune cell of claim 1 , wherein the CAR polypeptide comprises the amino acid sequence set forth in SEQ ID NO:6 or SEQ ID NO:7.
7 . The immune cell of claim 1 , wherein the immune cell is derived from a donor sample, or from a bank or library of donor samples.
8 . The method of claim 2 , wherein the B-lymphocyte antigen-associated cancer is a hematologic cancer selected from: acute leukemia, chronic leukemia, lymphocytic leukemia, myelogenous leukemia, a pre-leukemic condition, Hodgkin lymphoma, Non-Hodgkin lymphoma, an EBV-associated lymphoproliferative disease, mature B cell neoplasm, mature T cell or natural killer (NK) cell neoplasm, precursor lymphoid neoplasm, and immunodeficiency-associated lymphoproliferative disorder.
9 . The method of claim 2 , wherein the subject is human.