PMID- 19451549 OWN - NLM STAT- MEDLINE DCOM- 20090909 LR - 20231120 IS - 1528-0020 (Electronic) IS - 0006-4971 (Print) IS - 0006-4971 (Linking) VI - 114 IP - 3 DP - 2009 Jul 16 TI - Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. PG - 535-46 LID - 10.1182/blood-2009-03-211714 [doi] AB - 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. FAU - Johnson, Laura A AU - Johnson LA AD - Surgery Branch, Hatfield Clinical Research Center, National Cancer Institute/NIH, Bethesda, MD 20892, USA. FAU - Morgan, Richard A AU - Morgan RA FAU - Dudley, Mark E AU - Dudley ME FAU - Cassard, Lydie AU - Cassard L FAU - Yang, James C AU - Yang JC FAU - Hughes, Marybeth S AU - Hughes MS FAU - Kammula, Udai S AU - Kammula US FAU - Royal, Richard E AU - Royal RE FAU - Sherry, Richard M AU - Sherry RM FAU - Wunderlich, John R AU - Wunderlich JR FAU - Lee, Chyi-Chia R AU - Lee CC FAU - Restifo, Nicholas P AU - Restifo NP FAU - Schwarz, Susan L AU - Schwarz SL FAU - Cogdill, Alexandria P AU - Cogdill AP FAU - Bishop, Rachel J AU - Bishop RJ FAU - Kim, Hung AU - Kim H FAU - Brewer, Carmen C AU - Brewer CC FAU - Rudy, Susan F AU - Rudy SF FAU - VanWaes, Carter AU - VanWaes C FAU - Davis, Jeremy L AU - Davis JL FAU - Mathur, Aarti AU - Mathur A FAU - Ripley, Robert T AU - Ripley RT FAU - Nathan, Debbie A AU - Nathan DA FAU - Laurencot, Carolyn M AU - Laurencot CM FAU - Rosenberg, Steven A AU - Rosenberg SA LA - eng PT - Clinical Trial, Phase II PT - Journal Article DEP - 20090518 PL - United States TA - Blood JT - Blood JID - 7603509 RN - 0 (Antigens, Neoplasm) RN - 0 (Autoantigens) RN - 0 (Receptors, Antigen, T-Cell) SB - IM CIN - Expert Rev Vaccines. 2010 Apr;9(4):359-63. PMID: 20370546 MH - Adoptive Transfer/adverse effects/methods MH - Adult MH - Animals MH - Antigens, Neoplasm/*immunology MH - Autoantigens/immunology MH - Female MH - Genetic Therapy/*methods MH - Genetic Vectors MH - Hearing Loss/etiology MH - Humans MH - Lymphocyte Transfusion/adverse effects/methods MH - Lymphocytes/metabolism MH - Male MH - Melanocytes/immunology MH - Melanoma/complications/*therapy MH - Mice MH - Mice, Transgenic MH - Middle Aged MH - Receptors, Antigen, T-Cell/*administration & dosage/genetics/immunology MH - T-Cell Antigen Receptor Specificity MH - Transduction, Genetic MH - Transplantation, Autologous MH - Treatment Outcome MH - Uveitis/etiology PMC - PMC2929689 EDAT- 2009/05/20 09:00 MHDA- 2009/09/10 06:00 PMCR- 2009/07/16 CRDT- 2009/05/20 09:00 PHST- 2009/05/20 09:00 [entrez] PHST- 2009/05/20 09:00 [pubmed] PHST- 2009/09/10 06:00 [medline] PHST- 2009/07/16 00:00 [pmc-release] AID - S0006-4971(20)37049-X [pii] AID - 2009/211714 [pii] AID - 10.1182/blood-2009-03-211714 [doi] PST - ppublish SO - Blood. 2009 Jul 16;114(3):535-46. doi: 10.1182/blood-2009-03-211714. Epub 2009 May 18.