1. T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model.
- Author
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Di Stasi A, De Angelis B, Rooney CM, Zhang L, Mahendravada A, Foster AE, Heslop HE, Brenner MK, Dotti G, and Savoldo B
- Subjects
- Animals, Cell Line, Tumor, Chemokine CCL17 genetics, Chemokine CCL17 physiology, Chemokine CCL22 physiology, Cytotoxicity, Immunologic, Genetic Vectors genetics, Hodgkin Disease immunology, Hodgkin Disease pathology, Humans, Lymphocyte Activation, Lymphoma, Large-Cell, Anaplastic pathology, Mice, Mice, SCID, Receptors, CCR4 genetics, Receptors, Lymphocyte Homing, Recombinant Fusion Proteins physiology, Reed-Sternberg Cells chemistry, Th2 Cells immunology, Transduction, Genetic, Xenograft Model Antitumor Assays, Adoptive Transfer, Chemotaxis, Leukocyte, Hodgkin Disease therapy, Ki-1 Antigen physiology, Receptors, CCR4 physiology, T-Lymphocyte Subsets immunology
- Abstract
For the adoptive transfer of tumor-directed T lymphocytes to prove effective, there will probably need to be a match between the chemokines the tumor produces and the chemokine receptors the effector T cells express. The Reed-Stemberg cells of Hodgkin lymphoma (HL) predominantly produce thymus- and activation-regulated chemokine/CC chemokine ligand 17 (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22), which preferentially attract type 2 T helper (Th2) cells and regulatory T cells (Tregs) that express the TARC/MDC-specific chemokine receptor CCR4, thus generating an immunosuppressed tumor environment. By contrast, effector CD8(+) T cells lack CCR4, are nonresponsive to these chemokines and are rarely detected at the tumor site. We now show that forced expression of CCR4 by effector T cells enhances their migration to HL cells. Furthermore, T lymphocytes expressing both CCR4 and a chimeric antigen receptor directed to the HL associated antigen CD30 sustain their cytotoxic function and cytokine secretion in vitro, and produce enhanced tumor control when infused intravenously in mice engrafted with human HL. This approach may be of value in patients affected by HL.
- Published
- 2009
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