Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 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

Affiliations
Free PMC article
Clinical Trial

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

Nabil Ahmed et al. J Clin Oncol. .
Free PMC article

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.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

Figures

Fig 1.
Fig 1.
Plasma cytokine levels after human epidermal growth factor receptor 2 (HER2) chimeric antigen receptor (CAR) T-cell infusion. Plasma cytokine levels after HER2-CAR T-cell infusion were measured by multiplex analysis. Results for interferon gamma (IFNγ), tumor necrosis factor α (TNF-α), interleukin (IL) -6, and IL-8 are shown. There was a significant increase of plasma IL-8 levels at 1 (P = .028), 2 (P = .006), and 4 (P = .001) weeks after T-cell infusion. Results for granulocyte-macrophage colony-stimulating factor, IL-1β, IL-2, IL-4, IL-5, IL-7, IL-10, IL-12p70, and IL-13 are shown in Appendix Figure A2. pre, 3 hours (hr) and week (wk) 1, 2, 4, and 6 after infusion; ND, not detected.
Fig 2.
Fig 2.
In vivo persistence of human epidermal growth factor receptor 2 (HER2) chimeric antigen receptor (CAR) T cells. (A to C) In vivo persistence of T cells at each dose level (DL). (D) Correlation of cell dose and level of transgene detection 3 hours after HER2-CAR T-cell infusion. (E) Detection of HER2-CAR T cells 6 weeks after infusion was dependent on the infused T-cell dose (≤ v > 1 × 106/m2, P = .002). (F) HER2-CAR T cells were detected for up to 18 months after infusion.
Fig 3.
Fig 3.
Human epidermal growth factor receptor 2 (HER2) chimeric antigen receptor (CAR) T-cell homing to tumor sites. (A, C) patient 10; (B, D) patient 18. (A and B) Immunohistochemistry for CD3 expression in tumor biopsy. (C and D) Transgene detection in tumor biopsy and corresponding peripheral-blood sample.
Fig 4.
Fig 4.
Outcome after human epidermal growth factor receptor 2 (HER2) chimeric antigen receptor (CAR) T-cell infusion. (A) Kaplan-Meier curve of all infused patients (N = 19). (B) Prominent necrosis (patient 14) of tumor after HER2-CAR T-cell infusion. (C) Positron emission tomography images (patient 4) before (top arrow) and 6 weeks after (bottom arrow) HER2-CAR T-cell infusion.
Fig A1.
Fig A1.
Characterization of human epidermal growth factor receptor 2 (HER2) chimeric antigen receptor (CAR) T-cell product. (A) HER2-CAR expression on nontransduced (NT) and transduced T cells (NT v HER2-CAR T cells, P < .001). Individual data points and mean are shown. (B) Phenotypic analysis of HER2-CAR T-cell product. CM, central memory (CD3+/CD45RO+/CD62L+); EM, effector memory (CD3+/CD45RO+/CCR7/CD62L). Box plot with whiskers (Tukey method) is shown. (C) Cytotoxicity assay using NT and HER2-CAR T cells as effectors and HER2-negative (K562 and MDA-MB-468 [MDA]) or HER2-positive (NCI-H1299 and LM7) cell lines as targets. Mean with standard deviation at an effector-to-target ratio of 20:1 is shown. K562: NT v HER2-CAR T cells, P = not significant (NS); MDA: NT v HER2-CAR T cells, P = NS; NCI-H1229: NT v HER2-CAR T cells, P < .001; LM7: NT v HER2-CAR T cells, P < .001.
Fig A2.
Fig A2.
Plasma cytokine levels after human epidermal growth factor receptor 2 (HER2) chimeric antigen receptor (CAR) T-cell infusion. Plasma cytokine levels after HER2-CAR T-cell infusion were measured by multiplex analysis. (A) Results for granulocyte-macrophage colony-stimulating factor (GMCSF), interleukin (IL) -1β, IL-2, IL-4, IL-5; and (B) IL-7, IL-10, IL-12p70, and IL-13 are shown. There were no significant changes after T-cell infusion. Results for interferon gamma, tumor necrosis factor α, IL-6, and IL-8 are shown in Figure 1. ND, not detected.
Fig A3.
Fig A3.
In vivo persistence of T cells. Six patients received at least two doses of human epidermal growth factor receptor 2 (HER2) chimeric antigen receptor (CAR) T cells (shown for patients 5, 7, 12, 14, and 18). HER2-CAR T cells were detected by quantitative polymerase chain reaction after infusion. The pattern of HER2-CAR T-cell persistence was similar after both infusions. Left panel shows the data with a y axis maximum of 250 copies/μg DNA, and right panel shows the data with a y axis maximum of 50 copies/μg DNA.

Comment in

Similar articles

See all similar articles

Cited by 219 articles

See all "Cited by" articles

Publication types

MeSH terms

Feedback