Rhabdomyosarcoma lysis by T cells expressing a human autoantibody-based chimeric receptor targeting the fetal acetylcholine receptor.
Rhabdomyosarcomas are the most frequent malignant soft tissue tumors of childhood; however, because current multimodality treatments fail to improve the poor survival rate of children with metastatic rhabdomyosarcoma, new treatments are required. We previously identified the gamma-subunit of the fetal acetylcholine receptor (fAChR) as a specific cell surface target in rhabdomyosarcoma. Here, we engineered human T lymphocytes to express chimeric receptors composed of the antigen-binding domain of a human anti-fAChR antibody joined to the signaling domain of the human T-cell receptor zeta-chain. The interaction of fAChRzeta-transduced T cells with fAChR-positive rhabdomyosarcoma cell lines, but not with fAChR-negative control cells, induced T-cell activation characterized by strong secretion of IFN-gamma and delayed lysis of tumor cells. Importantly, we found that in six of six rhabdomyosarcoma patients, chemotherapy increased fAChR expression on residual tumor cells in vivo. Our observations suggest that these fully human chimeric fAChRzeta-transduced T cells, which should be well tolerated by the patient, have potential use in vivo both as a primary treatment for rhabdomyosarcoma and as a complementary approach to eradicate residual tumor cells after chemotherapy.
Gattenlöhner
Stefan
S
Institute of Pathology, University of Wuerzburg, Wuerzburg, Germany. stefan.gattenloehner@mail.uni-wuerzburg.de
Marx
Alexander
A
Markfort
Birgit
B
Pscherer
Sibylle
S
Landmeier
Silke
S
Juergens
Heribert
H
Müller-Hermelink
Hans-Konrad
HK
Matthews
Ian
I
Beeson
David
D
Vincent
Angela
A
Rossig
Claudia
C
D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D011950:Receptors, Cholinergic / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D012208:Rhabdomyosarcoma / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014161:Transduction, Genetic
D001323:Autoantibodies; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; D011950:Receptors, Cholinergic; D011993:Recombinant Fusion Proteins; C054979:antigen T cell receptor, zeta chain; D007371:Interferon-gamma