Development of human anti-murine T-cell receptor antibodies in both responding and nonresponding patients enrolled in TCR gene therapy trials

Jeremy L. Davis, Marc R. Theoret, Zhili Zheng, Cor H.J. Lamers, Steven A. Rosenberg, Richard A. Morgan

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: 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. Experimental Design: 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 α-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.

Original languageEnglish (US)
Pages (from-to)5852-5861
Number of pages10
JournalClinical Cancer Research
Volume16
Issue number23
DOIs
StatePublished - Dec 1 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Development of human anti-murine T-cell receptor antibodies in both responding and nonresponding patients enrolled in TCR gene therapy trials'. Together they form a unique fingerprint.

Cite this