Specific recognition and killing of glioblastoma multiforme by interleukin 13-zetakine redirected cytolytic T cells.
The interleukin (IL) 13 receptor alpha2 (IL13Ralpha2) is a glioma-restricted cell-surface epitope not otherwise detected within the central nervous system. Here, we describe a novel approach for targeting glioblastoma multiforme (GBM) with IL13Ralpha2-specific cytolytic T cells (CTLs) by their genetic modification to express a membrane-tethered IL13 cytokine chimeric T-cell antigen receptor, or zetakine. Our prototype zetakine incorporates an IL13 E13Y mutein for selective binding to IL13Ralpha2. Human IL13-zetakine(+)CD8(+) CTL transfectants display IL13Ralpha2-specific antitumor effector function including tumor cell cytolysis, T(C)1 cytokine production, and zetakine-regulated autocrine proliferation. The E13Y amino acid substitution of the IL13 mutein of the zetakine endows CTL transfectants with the capacity to discriminate between IL13Ralpha2(+) GBM targets from targets expressing IL13Ralpha1. In vivo, the adoptive transfer of IL13-zetakine(+)CD8(+) CTL clones results in the regression of established human glioblastoma orthotopic xenografts. Pilot clinical trials have been initiated to evaluate the feasibility and safety of local-regional delivery of autologous IL13-zetakine redirected CTL clones in patients with recurrent GBM. Our IL13-zetakine is a prototype of a new class of chimeric immunoreceptors that signal through an engineered immune synapse composed of membrane-tethered cytokine muteins bound to cell-surface cytokine receptors on tumors.
Kahlon
Kanwarpal S
KS
Division of Molecular Medicine, Beckman Research Institute, Departments of Pediatric Hematology-Oncology, City of Hope National Medical Center, Duarte, California, USA.
Brown
Christine
C
Cooper
Laurence J N
LJ
Raubitschek
Andrew
A
Forman
Stephen J
SJ
Jensen
Michael C
MC
D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor; D018076:DNA, Complementary / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005909:Glioblastoma / Q000276:immunology / Q000628:therapy*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053661:Interleukin-13 Receptor alpha1 Subunit; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000276:immunology; D053660:Receptors, Interleukin-13; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000502:physiology; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D018076:DNA, Complementary; D018984:Epitopes, T-Lymphocyte; C508181:IL13RA1 protein, human; C508183:Il13ra1 protein, mouse; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13