Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen

Blood - Tập 114 - Trang 535-546 - 2009
Laura A. Johnson1, Richard A. Morgan1, Mark E. Dudley1, Lydie Cassard1, James C. Yang1, Marybeth S. Hughes1, Udai S. Kammula1, Richard E. Royal1, Richard M. Sherry1, John R. Wunderlich1, Chyi-Chia R. Lee2, Nicholas P. Restifo1, Susan L. Schwarz1, Alexandria P. Cogdill1, Rachel J. Bishop3, Hung Kim4, Carmen C. Brewer4, Susan F. Rudy4, Carter VanWaes4, Jeremy L. Davis1
1Surgery Branch, National Cancer Institute (NCI), Hatfield Clinical Research Center, Bethesda, MD
2Laboratory of Pathology, NCI, Bethesda, MD
3Office of the Clinical Director, National Eye Institute, Bethesda, MD
4Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders, Bethesda, MD

Tóm tắt

Abstract Gene therapy of human cancer using genetically engineered lymphocytes is dependent on the identification of highly reactive T-cell receptors (TCRs) with antitumor activity. We immunized transgenic mice and also conducted high-throughput screening of human lymphocytes to generate TCRs highly reactive to melanoma/melanocyte antigens. Genes encoding these TCRs were engineered into retroviral vectors and used to transduce autologous peripheral lymphocytes administered to 36 patients with metastatic melanoma. Transduced patient lymphocytes were CD45RA− and CD45RO+ after ex vivo expansion. After infusion, the persisting cells displayed a CD45RA+ and CD45RO− phenotype. Gene-engineered cells persisted at high levels in the blood of all patients 1 month after treatment, responding patients with higher ex vivo antitumor reactivity than nonresponders. Objective cancer regressions were seen in 30% and 19% of patients who received the human or mouse TCR, respectively. However, patients exhibited destruction of normal melanocytes in the skin, eye, and ear, and sometimes required local steroid administration to treat uveitis and hearing loss. Thus, T cells expressing highly reactive TCRs mediate cancer regression in humans and target rare cognate–antigen-containing cells throughout the body, a finding with important implications for the gene therapy of cancer. This trial was registered at www.ClinicalTrials.gov as NCI-07-C-0174 and NCI-07-C-0175.

Tài liệu tham khảo

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Blood

Tập 114

535-546

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