Cancer regression in patients after transfer of genetically engineered lymphocytes
Richard A. Morgan,Mark E. Dudley,John R. Wunderlich,Michael S. Hughes,James Chih-Hsin Yang,Richard M. Sherry,Richard E. Royal,Suzanne L. Topalian,Udai S. Kammula,Nicholas P. Restifo,Zhili Zheng,Azam V. Nahvi,Christiaan R. de Vries,Linda Rogers-Freezer,Sharon Mavroukakis,Steven A. Rosenberg +15 more
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TLDR
The ability to specifically confer tumor recognition by autologous lymphocytes from peripheral blood by using a retrovirus that encodes a T cell receptor is reported.Abstract:
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.read more
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Cancer Regression and Autoimmunity in Patients After Clonal Repopulation with Antitumor Lymphocytes
Mark E. Dudley,John R. Wunderlich,Paul F. Robbins,James Chih-Hsin Yang,Patrick Hwu,Douglas J. Schwartzentruber,Suzanne L. Topalian,Richard M. Sherry,Nicholas P. Restifo,Amy M. Hubicki,Michael R. Robinson,Mark Raffeld,Paul H. Duray,Claudia A. Seipp,Linda Rogers-Freezer,Kathleen E. Morton,Sharon Mavroukakis,Donald E. White,Steven A. Rosenberg +18 more
TL;DR: The adoptive transfer of highly selected tumor-reactive T cells directed against overexpressed self-derived differentiation antigens after a nonmyeloablative conditioning regimen resulted in the persistent clonal repopulation of T cells in cancer patients, leading to regression of the patients' metastatic melanoma as well as to the onset of autoimmune melanocyte destruction.
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A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes
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Journal ArticleDOI
Adoptive Cell Transfer Therapy Following Non-Myeloablative but Lymphodepleting Chemotherapy for the Treatment of Patients With Refractory Metastatic Melanoma
Mark E. Dudley,John R. Wunderlich,James Chih-Hsin Yang,Richard M. Sherry,Suzanne L. Topalian,Nicholas P. Restifo,Richard E. Royal,Udai S. Kammula,Donald E. White,Sharon Mavroukakis,Linda J. Rogers,Gerald J. Gracia,Stephanie Jones,David P. Mangiameli,Michelle M. Pelletier,Juan Gea-Banacloche,Michael R. Robinson,David Berman,Armando C. Filie,Andrea Abati,Steven A. Rosenberg +20 more
TL;DR: Lymphodepleting chemotherapy followed by the transfer of highly avid antitumor lymphocytes can mediate significant tumor regression in heavily pretreated patients with IL-2 refractory metastatic melanoma.
Journal ArticleDOI
Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells
Luca Gattinoni,Steven E. Finkelstein,Christopher A. Klebanoff,Christopher A. Klebanoff,Paul A. Antony,Douglas C. Palmer,Paul J. Spiess,Leroy N. Hwang,Zhiya Yu,Claudia Wrzesinski,David M. Heimann,Charles D. Surh,Steven A. Rosenberg,Nicholas P. Restifo +13 more
TL;DR: It is found that even in the genetic absence of T reg cells, a nonmyeloablative regimen substantially augmented CD8+ T cell reactivity to self-tissue and tumor, and the restricted availability of homeostatic cytokines can be a contributing factor to peripheral tolerance, as well as a limiting resource for the effectiveness of tumor-specific T cells.
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