CHIMERIC ANTIGEN RECEPTORS (CARs) TARGETING HEMATOLOGIC MALIGNANCIES, COMPOSITIONS AND METHODS OF USE THEREOF
The present disclosure provides chimeric antigen receptor polypeptides having antigen recognition domains for CD2, CD3, CD4, CD5, CD7, CD8, and CD52 antigens, and polynucleotides encoding for the same. The present disclosure also provides for engineered cells expressing the polynucleotide or polypeptides. In some embodiments, the disclosure provides methods for treating diseases associated with CD2, CD3, CD4, CD5, CD7, CD8, and CD52 antigens.
1 .- 105 . (canceled)
106 . An engineered cell, said engineered cell comprises:
engineered chimeric antigen receptor polynucleotide, the polynucleotide encodes for a chimeric antigen receptor polypeptide comprising: a signal peptide, an antigen recognition domain, a hinge region, a transmembrane domain, at least one co-stimulatory domain, and a signaling domain; and wherein the antigen recognition domain is selected from the group consisting of CD2, CD3, CD4, CD5, CD7, CD8, and CD52.
107 . The engineered cell according to claim 106 , wherein the antigen recognition domain is selected from the group consisting of CD2, CD3, CD4, CD5, and CD7.
108 . The engineered cell according to claim 106 , wherein the engineered cell is deficient in at least one cell surface antigen selected from the group consisting of CD2, CD3, CD4, CD5, and CD7.
109 . The engineered cell according to claim 106 , wherein the engineered cell is deficient in a CD5 cell surface antigen.
110 . The engineered cell according to claim 106 , wherein the engineered cell is a T cell, NK T cell, or NK cell.
111 . The engineered cell according to claim 106 , wherein the antigen recognition domain is CD4; and the engineered cell is NK cell.
112 . The engineered cell according to claim 106 , wherein the hinge region comprises a CD8 hinge region.
113 . The engineered cell according to claim 106 , wherein the transmembrane region comprises a CD8 transmembrane region.
114 . The engineered cell according to claim 106 , wherein the transmembrane region comprises a CD28 transmembrane region.
115 . The engineered cell according to claim 106 , wherein the chimeric antigen receptor polypeptide comprises at least two co-stimulatory domains.
116 . The engineered cell according to claim 106 , wherein the chimeric antigen receptor polypeptide comprises a 4-1BB or CD28 co-stimulatory domain and a CD3zeta signaling domain.
117 . The engineered cell according to claim 106 , wherein the antigen recognition domain is selected from the group consisting of CD2, CD3, CD5, and CD7; and the engineered cell comprises a T cell that is deficient in a cell surface antigen selected from the group consisting of CD2, CD3, CD5, and CD7.
118 . The engineered cell according to claim 106 , wherein the antigen recognition domain is selected from the group consisting of CD2 and CD7; and the engineered cell comprises an NK cell that is deficient in a cell surface antigen selected from the group consisting of CD2 and CD7.
119 . The method according to claim 106 , wherein the CD2, CD3, CD5, or CD7 associated cell proliferative disease comprises precursor T lymphoblastic leukemia/lymphoma, mature T cell lymphomas/leukemias, EBV-positive T-cell lymphoproliferative disorders, adult T-cell leukemia/lymphoma, mycosis fungoides/sezary syndrome, primary cutaneous CD30-positive T-cell lymphoproliferative disorders, peripheral T-cell lymphoma (not otherwise specified), adult T cell lymphoma, T cell prolymphocytic leukemia, angioimmunoblastic T-cell lymphoma, or anaplastic large cell lymphoma.
120 . A method of generating a CD4CAR engineered cells, said method comprising the steps of:
obtaining a population of cells comprising CD4 T cells and CD8 T cells;
transforming the population of cells comprising CD4 T cells and CD8 T cells with a polynucleotide that encodes for a chimeric antigen receptor polypeptide comprising: a signal peptide, a CD4 antigen recognition domain, a hinge region, a transmembrane domain, at least one co-stimulatory domain, and a signaling domain; and
expanding the population of cells comprising CD4 T cells and CD8 T cells to provide CD4CAR engineered cells.
121 . The method according to claim 120 , wherein the population of CD4 T cells and CD8 T cells are obtained from human cord blood.
122 . The method according to claim 120 , wherein the CD4CAR engineered cells are CD8 T cells.
123 . The method according to claim 120 , wherein CD4 T cells are depleted.
124 . The method according to claim 120 , wherein the CD4CAR engineered cells are enriched for CD8 T cells and bear a central memory T cell like immunophenotype.
125 . The method according to claim 120 , wherein expanding comprises contacting the population of cells comprising CD4 T cells and CD8 T cells to at least one of IL-2, IL-7, and IL-15.
126 . The method according to claim 125 , wherein expanding occurs in vivo.
127 . The method according to claim 120 , further comprising isolating the CD4CAR engineered cells.
128 . A method of treating a CD4 associated cell proliferative disease in a human patient, said method comprising:
obtaining a population of cells comprising CD4 T cells and CD8 T cells;
transforming the population of cells comprising CD4 T cells and CD8 T cells with a polynucleotide that encodes for a chimeric antigen receptor polypeptide comprising: a signal peptide, a CD4 antigen recognition domain, a hinge region, a transmembrane domain, at least one co-stimulatory domain, and a signaling domain;
expanding the population of cells comprising CD4 T cells and CD8 T cells to provide CD4CAR engineered cells;
administering the CD4CAR engineered cells to the human patient; and
reducing the tumor burden of cell proliferative disease cells in the human patient.
129 . The method according to claim 128 , wherein the CD4 associated cell proliferative disease comprises acute myeloid leukemia, acute myelomonocytic leukemia, acute monoblastic leukemia, monocytic leukemia, or chronic myelomonocytic leukemia.
130 . The method according to claim 128 , wherein the CD4 associated cell proliferative disease comprises precursor T lymphoblastic leukemia/lymphoma, mature T cell lymphomas/leukemias, EBV-positive T-cell lymphoproliferative disorders, adult T-cell leukemia/lymphoma, mycosis fungoides/sezary syndrome, primary cutaneous CD30-positive T-cell lymphoproliferative disorders, peripheral T-cell lymphoma (not otherwise specified), adult T cell lymphoma, T cell prolymphocytic leukemia, angioimmunoblastic T-cell lymphoma, or anaplastic large cell lymphoma.
131 . The method according to claim 128 , wherein the method further comprises administration in conjunction with one or more of chemotherapy, radiation, immunosuppressive agents, and antiviral therapy.
132 . The method according to claim 128 , wherein expanding comprises contacting the population of cells comprising CD4 T cells and CD8 T cells to at least one of IL-2, IL-7, and IL-15.
133 . The method according to claim 132 , wherein expanding occurs in vivo.
134 . The method according to claim 128 , wherein administering further comprises co-administering with at least one of cytokines, inhibitors of colony stimulating factor-1 receptor (CSF1R), cyclosporin, azathioprine, methotrexate, mycophenolate, CAMPATH, antibody, anti-CD3 antibody, cytoxin, fludarabine, cyclosporin, FK506, rapamycin, mycophenolic acid, steroids, and FR901228.