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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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   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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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 »
Biology by design: reduction and synthesis of cellular components and behaviour.
P. Marguet, F. Balagadde, C. Tan, and L. You (2007)
J R Soc Interface 4, 607-623
   Abstract »    Full Text »    PDF »
In vivo imaging of T cell delivery to tumors after adoptive transfer therapy.
M. J. Pittet, J. Grimm, C. R. Berger, T. Tamura, G. Wojtkiewicz, M. Nahrendorf, P. Romero, F. K. Swirski, and R. Weissleder (2007)
PNAS 104, 12457-12461
   Abstract »    Full Text »    PDF »
Cancer Vaccines: Moving Beyond Current Paradigms.
J. Schlom, P. M. Arlen, and J. L. Gulley (2007)
Clin. Cancer Res. 13, 3776-3782
   Abstract »    Full Text »    PDF »
Signal 3 Availability Limits the CD8 T Cell Response to a Solid Tumor.
J. M. Curtsinger, M. Y. Gerner, D. C. Lins, and M. F. Mescher (2007)
J. Immunol. 178, 6752-6760
   Abstract »    Full Text »    PDF »
Functional Up-regulation of Human Leukocyte Antigen Class I Antigens Expression by 5-aza-2'-deoxycytidine in Cutaneous Melanoma: Immunotherapeutic Implications.
E. Fonsatti, H. J.M. Nicolay, L. Sigalotti, L. Calabro, L. Pezzani, F. Colizzi, M. Altomonte, M. Guidoboni, F. M. Marincola, and M. Maio (2007)
Clin. Cancer Res. 13, 3333-3338
   Abstract »    Full Text »    PDF »
T-Cell Distribution and Adhesion Receptor Expression in Metastatic Melanoma.
C. Weishaupt, K. N. Munoz, E. Buzney, T. S. Kupper, and R. C. Fuhlbrigge (2007)
Clin. Cancer Res. 13, 2549-2556
   Abstract »    Full Text »    PDF »
Enhanced Antitumor Activity of T Cells Engineered to Express T-Cell Receptors with a Second Disulfide Bond.
C. J. Cohen, Y. F. Li, M. El-Gamil, P. F. Robbins, S. A. Rosenberg, and R. A. Morgan (2007)
Cancer Res. 67, 3898-3903
   Abstract »    Full Text »    PDF »
CpG oligodeoxynucleotides allow for effective adoptive T-cell therapy in chronic retroviral infection.
A. R. M. Kraft, F. Krux, S. Schimmer, C. Ohlen, P. D. Greenberg, and U. Dittmer (2007)
Blood 109, 2982-2984
   Abstract »    Full Text »    PDF »
Extrathymic Generation of Tumor-Specific T Cells from Genetically Engineered Human Hematopoietic Stem Cells via Notch Signaling.
Y. Zhao, M. R. Parkhurst, Z. Zheng, C. J. Cohen, J. P. Riley, L. Gattinoni, N. P. Restifo, S. A. Rosenberg, and R. A. Morgan (2007)
Cancer Res. 67, 2425-2429
   Abstract »    Full Text »    PDF »
Facilitating matched pairing and expression of TCR chains introduced into human T cells.
J. Kuball, M. L. Dossett, M. Wolfl, W. Y. Ho, R.-H. Voss, C. Fowler, and P. D. Greenberg (2007)
Blood 109, 2331-2338
   Abstract »    Full Text »    PDF »
Chimeric T-cell receptors: new challenges for targeted immunotherapy in hematologic malignancies.
E. Biagi, V. Marin, G. M. P. Giordano Attianese, E. Dander, G. D'Amico, and A. Biondi (2007)
Haematologica 92, 381-388
   Abstract »    Full Text »    PDF »
Concise Review: Cancer/Testis Antigens, Stem Cells, and Cancer.
F. F. Costa, K. Le Blanc, and B. Brodin (2007)
Stem Cells 25, 707-711
   Abstract »    Full Text »    PDF »
Induced sensitization of tumor stroma leads to eradication of established cancer by T cells.
B. Zhang, N. A. Bowerman, J. K. Salama, H. Schmidt, M. T. Spiotto, A. Schietinger, P. Yu, Y.-X. Fu, R. R. Weichselbaum, D. A. Rowley, et al. (2007)
J. Exp. Med. 204, 49-55
   Abstract »    Full Text »    PDF »


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