Compositions and methods for treating cancer with DuoCARs
Novel therapeutic immunotherapy compositions comprising at least two vectors, each vector encoding a functional CAR, whereby the combination of vectors results in the expression of two or more non-identical binding domains, wherein each vector encoded binding domain(s) are covalently linked to a transmembrane domain and one or more non-identical intracellular signaling motifs are provided herein as well as are methods of use of same in a patient-specific immunotherapy that can be used to treat cancers and other diseases and conditions.
1. An immunotherapy composition comprising: at least one multicistronic vector comprising a promoter operably linked to a multi-cistronic nucleic acid sequence encoding two or more functional CARs comprising an extracellular antigen binding domain, a transmembrane domain, one or more non-identical intracellular signaling motifs, wherein each of the encoded two or more functional CARs comprises a non-identical amino acid sequence that is independently selected from the group consisting of the amino acid sequence of SEQ ID NO:110, 112, 114, and 116;
and wherein the at least one multi-cistronic vector is used to genetically modify one or more lymphocyte populations.
2. The immunotherapy composition of claim 1 , wherein the extracellular antigen binding domain of each of the two or more functional CARs targets an antigen comprising CD19, CD20, CD22, ROR1, TSLPR, mesothelin, CD33, CD38, CD123 (IL3RA), CD138, BCMA (CD269), GPC2, GPC3, FGFR4, c-Met, PSMA, Glycolipid F77, EGFRVIII, GD-2, NY-ESO-1 TCR, MAGE A3 TCR, or any combination thereof.
3. A pharmaceutical composition comprising an antitumor effective amount of a population of isolated human lymphocyte cells, wherein the cells of the population include cells comprising (a) nucleic acid molecules encoding at least one multicistronic vector; (b) wherein the at least one multicistronic vector comprises a promoter operably linked to a multicistronic nucleic acid sequence encoding two or more functional CARs comprising an extracellular antigen binding domain, a transmembrane domain, one or more non-identical intracellular signaling motifs, wherein each of the encoded two or more functional CARs comprises a non-identical amino acid sequence that is independently selected from the group consisting of the amino acid sequence of SEQ ID NO: 110, 112, 114, and 116, wherein the at least one multicistronic vector is used to genetically modify the population of human lymphocyte cells.
4. The pharmaceutical composition of claim 3 , wherein the population of isolated human lymphocytes are isolated T cells of a human having leukemia or lymphoma.
5. The pharmaceutical composition of claim 4 , wherein the leukemia is chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), or chronic myelogenous leukemia (CML).
6. The pharmaceutical composition of claim 4 , wherein the lymphoma is mantle cell lymphoma, non-Hodgkin's lymphoma or Hodgkin's lymphoma.
7. The pharmaceutical composition of claim 3 , wherein the population of isolated human lymphocytes are isolated T cells of a human having multiple myeloma.
8. The pharmaceutical composition of claim 3 , wherein the population of human lymphocytes are T cells of a human having 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, and endocrine cancer, and a brain cancer.