Human epidermal growth factor receptor 2 (HER2) - Specific chimeric antigen receptor - Modified T cells for the immunotherapy of HER2-positive sarcoma

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. RooneyMalcolm K. Brenner, Helen E. Heslop, Winfried S. Wels, Lisa L. Wang, Peter Anderson, Stephen Gottschalk

Research output: Contribution to journalArticlepeer-review

431 Scopus citations

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 × 104/m2 to 1 × 108/m2) of T cells expressing an HER2-specific chimeric antigen receptor with a CD28.ô 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 × 105/m2) 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 × 106/m2 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.

Original languageEnglish (US)
Pages (from-to)1688-1696
Number of pages9
JournalJournal of Clinical Oncology
Volume33
Issue number15
DOIs
StatePublished - May 20 2015
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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