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J Clin Oncol. 2015 May 20;33(15):1688-96. doi: 10.1200/JCO.2014.58.0225. Epub 2015 Mar 23.

Human Epidermal Growth Factor Receptor 2 (HER2) -Specific Chimeric Antigen Receptor-Modified T Cells for the Immunotherapy of HER2-Positive Sarcoma.

Author information

1
Nabil Ahmed, Vita S. Brawley, Meenakshi Hegde, Catherine Robertson, Alexia Ghazi, Claudia Gerken, Enli Liu, Olga Dakhova, Aidin Ashoori, Amanda Corder, Tara Gray, Gianpietro Dotti, Zhuyong Mei, Bambi Grilley, Adrian Gee, Cliona M. Rooney, Malcolm K. Brenner, Helen E. Heslop, and Stephen Gottschalk, Center for Cell and Gene Therapy, Texas Children's Hospital, Baylor College of Medicine, Houston Methodist Hospital; Nabil Ahmed, Vita S. Brawley, Meenakshi Hegde, Catherine Robertson, Alexia Ghazi, Claudia Gerken, Enli Liu, Olga Dakhova, Aidin Ashoori, Amanda Corder, Tara Gray, John Hicks, Nino Rainusso, Zhuyong Mei, Bambi Grilley, Adrian Gee, Cliona M. Rooney, Malcolm K. Brenner, Helen E. Heslop, Lisa L. Wang, and Stephen Gottschalk, Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine; Nabil Ahmed, Vita S. Brawley, Meenakshi Hegde, Catherine Robertson, Alexia Ghazi, Claudia Gerken, Enli Liu, Olga Dakhova, Aidin Ashoori, Amanda Corder, Tara Gray, Meng-Fen Wu, Hao Liu, John Hicks, Nino Rainusso, Gianpietro Dotti, Zhuyong Mei, Bambi Grilley, Adrian Gee, Cliona M. Rooney, Malcolm K. Brenner, Helen E. Heslop, Lisa L. Wang, and Stephen Gottschalk, Baylor College of Medicine; Peter Anderson, The University of Texas MD Anderson Cancer Center, Houston, TX; Peter Anderson, Levine Children's Hospital, Levine Cancer Institute, Carolinas Healthcare System, Charlotte NC; and Winfried S. Wels, Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt, Germany.
2
Nabil Ahmed, Vita S. Brawley, Meenakshi Hegde, Catherine Robertson, Alexia Ghazi, Claudia Gerken, Enli Liu, Olga Dakhova, Aidin Ashoori, Amanda Corder, Tara Gray, Gianpietro Dotti, Zhuyong Mei, Bambi Grilley, Adrian Gee, Cliona M. Rooney, Malcolm K. Brenner, Helen E. Heslop, and Stephen Gottschalk, Center for Cell and Gene Therapy, Texas Children's Hospital, Baylor College of Medicine, Houston Methodist Hospital; Nabil Ahmed, Vita S. Brawley, Meenakshi Hegde, Catherine Robertson, Alexia Ghazi, Claudia Gerken, Enli Liu, Olga Dakhova, Aidin Ashoori, Amanda Corder, Tara Gray, John Hicks, Nino Rainusso, Zhuyong Mei, Bambi Grilley, Adrian Gee, Cliona M. Rooney, Malcolm K. Brenner, Helen E. Heslop, Lisa L. Wang, and Stephen Gottschalk, Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine; Nabil Ahmed, Vita S. Brawley, Meenakshi Hegde, Catherine Robertson, Alexia Ghazi, Claudia Gerken, Enli Liu, Olga Dakhova, Aidin Ashoori, Amanda Corder, Tara Gray, Meng-Fen Wu, Hao Liu, John Hicks, Nino Rainusso, Gianpietro Dotti, Zhuyong Mei, Bambi Grilley, Adrian Gee, Cliona M. Rooney, Malcolm K. Brenner, Helen E. Heslop, Lisa L. Wang, and Stephen Gottschalk, Baylor College of Medicine; Peter Anderson, The University of Texas MD Anderson Cancer Center, Houston, TX; Peter Anderson, Levine Children's Hospital, Levine Cancer Institute, Carolinas Healthcare System, Charlotte NC; and Winfried S. Wels, Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt, Germany. smgottsc@txch.org.

Abstract

PURPOSE:

The outcome for patients with metastatic or recurrent sarcoma remains poor. Adoptive therapy with tumor-directed T cells is an attractive therapeutic option but has never been evaluated in sarcoma.

PATIENTS AND METHODS:

We conducted a phase I/II clinical study in which patients with recurrent/refractory human epidermal growth factor receptor 2 (HER2) -positive sarcoma received escalating doses (1 × 10(4)/m(2) to 1 × 10(8)/m(2)) of T cells expressing an HER2-specific chimeric antigen receptor with a CD28.ζ signaling domain (HER2-CAR T cells).

RESULTS:

We enrolled 19 patients with HER2-positive tumors (16 osteosarcomas, one Ewing sarcoma, one primitive neuroectodermal tumor, and one desmoplastic small round cell tumor). HER2-CAR T-cell infusions were well tolerated with no dose-limiting toxicity. At dose level 3 (1 × 10(5)/m(2)) and above, we detected HER2-CAR T cells 3 hours after infusion by quantitative polymerase chain reaction in 14 of 16 patients. HER2-CAR T cells persisted for at least 6 weeks in seven of the nine evaluable patients who received greater than 1 × 10(6)/m(2) HER2-CAR T cells (P = .005). HER2-CAR T cells were detected at tumor sites of two of two patients examined. Of 17 evaluable patients, four had stable disease for 12 weeks to 14 months. Three of these patients had their tumor removed, with one showing ≥ 90% necrosis. The median overall survival of all 19 infused patients was 10.3 months (range, 5.1 to 29.1 months).

CONCLUSION:

This first evaluation of the safety and efficacy of HER2-CAR T cells in patients with cancer shows the cells can persist for 6 weeks without evident toxicities, setting the stage for studies that combine HER2-CAR T cells with other immunomodulatory approaches to enhance their expansion and persistence.

PMID:
25800760
PMCID:
PMC4429176
DOI:
10.1200/JCO.2014.58.0225
[Indexed for MEDLINE]
Free PMC Article

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