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Originally published in Science Express on 31 August 2006
Science 6 October 2006:
Vol. 314. no. 5796, pp. 126 - 129
DOI: 10.1126/science.1129003
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Reports

Cancer Regression in Patients After Transfer of Genetically Engineered Lymphocytes

Richard A. Morgan, Mark E. Dudley, John R. Wunderlich, Marybeth S. Hughes, James C. Yang, Richard M. Sherry, Richard E. Royal, Suzanne L. Topalian, Udai S. Kammula, Nicholas P. Restifo, Zhili Zheng, Azam Nahvi, Christiaan R. de Vries, Linda J. Rogers-Freezer, Sharon A. Mavroukakis, Steven A. Rosenberg*

Through the adoptive transfer of lymphocytes after host immunodepletion, it is possible to mediate objective cancer regression in human patients with metastatic melanoma. However, the generation of tumor-specific T cells in this mode of immunotherapy is often limiting. Here we report the ability to specifically confer tumor recognition by autologous lymphocytes from peripheral blood by using a retrovirus that encodes a T cell receptor. Adoptive transfer of these transduced cells in 15 patients resulted in durable engraftment at levels exceeding 10% of peripheral blood lymphocytes for at least 2 months after the infusion. We observed high sustained levels of circulating, engineered cells at 1 year after infusion in two patients who both demonstrated objective regression of metastatic melanoma lesions. This study suggests the therapeutic potential of genetically engineered cells for the biologic therapy of cancer.

Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA.

* To whom correspondence should be addressed. E-mail: SAR{at}mail.nih.gov

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Gene Therapy Shows Promise Against Melanoma

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Selecting highly affine and well-expressed TCRs for gene therapy of melanoma.
A. Jorritsma, R. Gomez-Eerland, M. Dokter, W. van de Kasteele, Y. M. Zoet, I. I. N. Doxiadis, N. Rufer, P. Romero, R. A. Morgan, T. N. M. Schumacher, et al. (2007)
Blood 110, 3564-3572
   Abstract »    Full Text »    PDF »
Enhanced Activation of Human Dendritic Cells by Inducible CD40 and Toll-like Receptor-4 Ligation.
N. Lapteva, M. R. Seethammagari, B. A. Hanks, J. Jiang, J. M. Levitt, K. M. Slawin, and D. M. Spencer (2007)
Cancer Res. 67, 10528-10537
   Abstract »    Full Text »    PDF »
Targeting the Wilms Tumor Antigen 1 by TCR Gene Transfer: TCR Variants Improve Tetramer Binding but Not the Function of Gene Modified Human T Cells.
S. Thomas, S.-A. Xue, M. Cesco-Gaspere, E. San Jose, D. P. Hart, V. Wong, R. Debets, B. Alarcon, E. Morris, and H. J. Stauss (2007)
J. Immunol. 179, 5803-5810
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High-Affinity TCRs Generated by Phage Display Provide CD4+ T Cells with the Ability to Recognize and Kill Tumor Cell Lines.
Y. Zhao, A. D. Bennett, Z. Zheng, Q. J. Wang, P. F. Robbins, L. Y. L. Yu, Y. Li, P. E. Molloy, S. M. Dunn, B. K. Jakobsen, et al. (2007)
J. Immunol. 179, 5845-5854
   Abstract »    Full Text »    PDF »
Identification of a Novel Cancer-Testis Antigen CRT2 Frequently Expressed in Various Cancers Using Representational Differential Analysis.
E. Hayashi, Y. Matsuzaki, G. Hasegawa, T. Yaguchi, S. Kurihara, T. Fujita, T. Kageshita, M. Sano, and Y. Kawakami (2007)
Clin. Cancer Res. 13, 6267-6274
   Abstract »    Full Text »    PDF »
Update on clinical gene therapy in childhood.
W. Qasim, H Bobby Gaspar, and A. J Thrasher (2007)
Arch. Dis. Child. 92, 1028-1031
   Abstract »    Full Text »    PDF »
Cross-presentation of glycolipid from tumor cells loaded with {alpha}-galactosylceramide leads to potent and long-lived T cell mediated immunity via dendritic cells.
K. Shimizu, Y. Kurosawa, M. Taniguchi, R. M. Steinman, and S.-i. Fujii (2007)
J. Exp. Med. 204, 2641-2653
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Functional Human Antigen-Specific T Cells Produced In Vitro Using Retroviral T Cell Receptor Transfer into Hematopoietic Progenitors.
A. U. van Lent, M. Nagasawa, M. M. van Loenen, R. Schotte, T. N. M. Schumacher, M. H. M. Heemskerk, H. Spits, and N. Legrand (2007)
J. Immunol. 179, 4959-4968
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Dual T Cell Receptor Expressing CD8+ T Cells with Tumor- and Self-Specificity Can Inhibit Tumor Growth without Causing Severe Autoimmunity.
M. Weinhold, D. Sommermeyer, W. Uckert, and T. Blankenstein (2007)
J. Immunol. 179, 5534-5542
   Abstract »    Full Text »    PDF »
Warrior, miscreant, suicide: making better killers.
M. E. Dudley (2007)
Blood 110, 2781-2782
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Complete responses of relapsed lymphoma following genetic modification of tumor-antigen presenting cells and T-lymphocyte transfer.
C. M. Bollard, S. Gottschalk, A. M. Leen, H. Weiss, K. C. Straathof, G. Carrum, M. Khalil, M.-f. Wu, M. H. Huls, C.-C. Chang, et al. (2007)
Blood 110, 2838-2845
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Allorestricted T cells with specificity for the FMNL1-derived peptide PP2 have potent antitumor activity against hematologic and other malignancies.
I. G. Schuster, D. H. Busch, E. Eppinger, E. Kremmer, S. Milosevic, C. Hennard, C. Kuttler, J. W. Ellwart, B. Frankenberger, E. Nossner, et al. (2007)
Blood 110, 2931-2939
   Abstract »    Full Text »    PDF »
A Comparison and Critical Analysis of Preclinical Anticancer Vaccination Strategies.
J. N. Kochenderfer and R. E. Gress (2007)
Experimental Biology and Medicine 232, 1130-1141
   Abstract »    Full Text »    PDF »
IL-21 synergizes with IL-7 to augment expansion and anti-tumor function of cytotoxic T cells.
S. Liu, G. Lizee, Y. Lou, C. Liu, W. W. Overwijk, G. Wang, and P. Hwu (2007)
Int. Immunol. 19, 1213-1221
   Abstract »    Full Text »    PDF »
Epstein Barr virus specific cytotoxic T lymphocytes expressing the anti-CD30{zeta} artificial chimeric T-cell receptor for immunotherapy of Hodgkin disease.
B. Savoldo, C. M. Rooney, A. Di Stasi, H. Abken, A. Hombach, A. E. Foster, L. Zhang, H. E. Heslop, M. K. Brenner, and G. Dotti (2007)
Blood 110, 2620-2630
   Abstract »    Full Text »    PDF »
Toll-like Receptors in Tumor Immunotherapy.
C. M. Paulos, A. Kaiser, C. Wrzesinski, C. S. Hinrichs, L. Cassard, A. Boni, P. Muranski, L. Sanchez-Perez, D. C. Palmer, Z. Yu, et al. (2007)
Clin. Cancer Res. 13, 5280-5289
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Gene-Engineered Varicella-Zoster Virus Reactive CD4+ Cytotoxic T Cells Exert Tumor-Specific Effector Function.
S. Landmeier, B. Altvater, S. Pscherer, B. R. Eing, J. Kuehn, C. M. Rooney, H. Juergens, and C. Rossig (2007)
Cancer Res. 67, 8335-8343
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Tumor-Derived Chemokine MCP-1/CCL2 Is Sufficient for Mediating Tumor Tropism of Adoptively Transferred T Cells.
C. E. Brown, R. P. Vishwanath, B. Aguilar, R. Starr, J. Najbauer, K. S. Aboody, and M. C. Jensen (2007)
J. Immunol. 179, 3332-3341
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Chimeric immune receptors (CIRs) specific to JC virus for immunotherapy in progressive multifocal leukoencephalopathy (PML).
W Yang, E. Beaudoin, L Lu, R. Du Pasquier, M. Kuroda, R. Willemsen, I. Koralnik, and R. Junghans (2007)
Int. Immunol. 19, 1083-1093
   Abstract »    Full Text »    PDF »


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