Development of human anti-murine T-cell receptor antibodies in both responding and nonresponding patients enrolled in TCR gene therapy trials.
OBJECTIVE
Immune responses to gene-modified cells are a concern in the field of human gene therapy, as they may impede effective treatment. We conducted 2 clinical trials in which cancer patients were treated with lymphocytes genetically engineered to express murine T-cell receptors (mTCR) specific for tumor-associated antigens p53 and gp100.


METHODS
Twenty-six patients treated with autologous lymphocytes expressing mTCR had blood and serum samples available for analysis. Patient sera were assayed for the development of a humoral immune response. Adoptive cell transfer characteristics were analyzed to identify correlates to immune response.


RESULTS
Six of 26 (23%) patients' posttreatment sera exhibited specific binding of human anti-mTCR antibodies to lymphocytes transduced with the mTCR. Antibody development was found in both responding and nonresponding patients. The posttreatment sera of 3 of these 6 patients mediated a 60% to 99% inhibition of mTCR activity as measured by a reduction in antigen-specific interferon-γ release. Detailed analysis of posttreatment serum revealed that antibody binding was β-chain specific in 1 patient whereas it was α-chain specific in another.


CONCLUSIONS
A subset of patients treated with mTCR-engineered T cells developed antibodies directed to the mTCR variable regions and not to the constant region domains common to all mTCR. Overall, the development of a host immune response was not associated with the level of transduced cell persistence or response to therapy. In summary, patients treated with mTCR can develop an immune response to gene-modified cells in a minority of cases, but this may not affect clinical outcome.
Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Jeremy L
JL
Davis
Marc R
MR
Theoret
Zhili
Z
Zheng
Cor H J
CH
Lamers
Steven A
SA
Rosenberg
Richard A
RA
Morgan
D019264:Adoptive Transfer / Q000009:adverse effects / Q000379:methods; D000328:Adult; D000818:Animals; D000906:Antibodies / Q000378:metabolism*; D000917:Antibody Formation / Q000502:physiology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology; D002986:Clinical Trials as Topic; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology*; D013045:Species Specificity; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D000906:Antibodies; D019496:Cancer Vaccines; D011948:Receptors, Antigen, T-Cell