title: Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma.
abstract: An obstacle to cancer immunotherapy has been that the affinity of T-cell receptors (TCRs) for antigens expressed in tumors is generally low. We initiated clinical testing of engineered T cells expressing an affinity-enhanced TCR against HLA-A*01-restricted MAGE-A3. Open-label protocols to test the TCRs for patients with myeloma and melanoma were initiated. The first two treated patients developed cardiogenic shock and died within a few days of T-cell infusion, events not predicted by preclinical studies of the high-affinity TCRs. Gross findings at autopsy revealed severe myocardial damage, and histopathological analysis revealed T-cell infiltration. No MAGE-A3 expression was detected in heart autopsy tissues. Robust proliferation of the engineered T cells in vivo was documented in both patients. A beating cardiomyocyte culture generated from induced pluripotent stem cells triggered T-cell killing, which was due to recognition of an unrelated peptide derived from the striated muscle-specific protein titin. These patients demonstrate that TCR-engineered T cells can have serious and not readily predictable off-target and organ-specific toxicities and highlight the need for improved methods to define the specificity of engineered TCRs.
authors.affiliation: Siteman Cancer Center and Departments of Medicine and Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Gerald P
authors.initials: GP
authors.lastname: Linette
authors.forename: Edward A
authors.initials: EA
authors.lastname: Stadtmauer
authors.forename: Marcela V
authors.initials: MV
authors.lastname: Maus
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Rapoport
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Levine
authors.forename: Lyndsey
authors.initials: L
authors.lastname: Emery
authors.forename: Leslie
authors.initials: L
authors.lastname: Litzky
authors.forename: Adam
authors.initials: A
authors.lastname: Bagg
authors.forename: Beatriz M
authors.initials: BM
authors.lastname: Carreno
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Cimino
authors.forename: Gwendolyn K
authors.initials: GK
authors.lastname: Binder-Scholl
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Smethurst
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Gerry
authors.forename: Nick J
authors.initials: NJ
authors.lastname: Pumphrey
authors.forename: Alan D
authors.initials: AD
authors.lastname: Bennett
authors.forename: Joanna E
authors.initials: JE
authors.lastname: Brewer
authors.forename: Joseph
authors.initials: J
authors.lastname: Dukes
authors.forename: Jane
authors.initials: J
authors.lastname: Harper
authors.forename: Helen K
authors.initials: HK
authors.lastname: Tayton-Martin
authors.forename: Bent K
authors.initials: BK
authors.lastname: Jakobsen
authors.forename: Namir J
authors.initials: NJ
authors.lastname: Hassan
authors.forename: Michael
authors.initials: M
authors.lastname: Kalos
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
mesh_terms: D000483:Alleles; D020816:Amino Acid Motifs; D000951:Antigens, Neoplasm / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000150:complications*; D018929:Cell Culture Techniques; D064211:Connectin; D016207:Cytokines / Q000378:metabolism; D000939:Epitopes / Q000378:metabolism; D015234:HLA-A Antigens / Q000378:metabolism; D006801:Humans; D016219:Immunotherapy, Adoptive; D057026:Induced Pluripotent Stem Cells / Q000166:cytology; D008297:Male; D008545:Melanoma / Q000097:blood* / Q000628:therapy; D008875:Middle Aged; D009101:Multiple Myeloma / Q000097:blood* / Q000628:therapy; D009124:Muscle Proteins / Q000378:metabolism*; D009206:Myocardium / Q000276:immunology / Q000473:pathology*; D009363:Neoplasm Proteins / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D015202:Protein Engineering; D011494:Protein Kinases / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology*
chemical_list: D000951:Antigens, Neoplasm; D064211:Connectin; D016207:Cytokines; D000939:Epitopes; D015234:HLA-A Antigens; C072013:MAGEA3 protein, human; D009124:Muscle Proteins; D009363:Neoplasm Proteins; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; C577285:TTN protein, human; D011494:Protein Kinases