Abstract
Genetically targeted T cells promise to solve the feasibility and efficacy hurdles of adoptive T-cell therapy for cancer. Selecting a target expressed in multiple-tumor types and that is required for tumor growth would widen disease indications and prevent immune escape caused by the emergence of antigen-loss variants. The adhesive receptor CD44 is broadly expressed in hematologic and epithelial tumors, where it contributes to the cancer stem/initiating phenotype. In this study, silencing of its isoform variant 6 (CD44v6) prevented engraftment of human acute myeloid leukemia (AML) and multiple myeloma (MM) cells in immunocompromised mice. Accordingly, T cells targeted to CD44v6 by means of a chimeric antigen receptor containing a CD28 signaling domain mediated potent antitumor effects against primary AML and MM while sparing normal hematopoietic stem cells and CD44v6-expressing keratinocytes. Importantly, in vitro activation with CD3/CD28 beads and interleukin (IL)-7/IL-15 was required for antitumor efficacy in vivo. Finally, coexpressing a suicide gene enabled fast and efficient pharmacologic ablation of CD44v6-targeted T cells and complete rescue from hyperacute xenogeneic graft-versus-host disease modeling early and generalized toxicity. These results warrant the clinical investigation of suicidal CD44v6-targeted T cells in AML and MM.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Neoplasm / genetics
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Antigens, Neoplasm / immunology*
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CD28 Antigens / immunology
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CD3 Complex / immunology
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Cell Line, Tumor / immunology
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Cell Line, Tumor / transplantation
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Cytotoxicity, Immunologic
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Genes, Transgenic, Suicide
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Graft vs Host Disease / therapy
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Humans
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Hyaluronan Receptors / genetics
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Hyaluronan Receptors / immunology*
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Immunotherapy, Adoptive*
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Interleukin-15 / immunology
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Interleukin-15 / pharmacology
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Interleukin-7 / immunology
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Interleukin-7 / pharmacology
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Leukemia, Myeloid, Acute / immunology
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Leukemia, Myeloid, Acute / pathology
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Leukemia, Myeloid, Acute / therapy*
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Leukemia, Myelomonocytic, Acute / immunology
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Leukemia, Myelomonocytic, Acute / pathology
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Leukemia, Myelomonocytic, Acute / therapy
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Lymphocyte Activation
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Mice
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Molecular Targeted Therapy*
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Multiple Myeloma / immunology
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Multiple Myeloma / pathology
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Multiple Myeloma / therapy*
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Neoplasm Transplantation
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Protein Structure, Tertiary
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RNA, Small Interfering / pharmacology
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Recombinant Fusion Proteins / immunology
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T-Cell Antigen Receptor Specificity
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T-Lymphocyte Subsets / immunology*
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Xenograft Model Antitumor Assays
Substances
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Antigens, Neoplasm
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CD28 Antigens
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CD3 Complex
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CD44v6 antigen
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Hyaluronan Receptors
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IL15 protein, human
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IL7 protein, human
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Interleukin-15
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Interleukin-7
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RNA, Small Interfering
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Recombinant Fusion Proteins