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01.12.2018 | Research | Ausgabe 1/2018 Open Access

Journal of Hematology & Oncology 1/2018

Anti-GD2/4-1BB chimeric antigen receptor T cell therapy for the treatment of Chinese melanoma patients

Zeitschrift:
Journal of Hematology & Oncology > Ausgabe 1/2018
Autoren:
Jiayi Yu, Xiaowen Wu, Junya Yan, Huan Yu, Longwen Xu, Zhihong Chi, Xinan Sheng, Lu Si, Chuanliang Cui, Jie Dai, Meng Ma, Tianxiao Xu, Yan Kong, Jun Guo
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s13045-017-0548-2) contains supplementary material, which is available to authorized users.

Abstract

Background

Chimeric antigen receptor (CAR)-engineered T cells have demonstrated promising clinical efficacy in patients with B cell lymphoma. However, the application of CAR-T cell therapy in the treatment of other solid tumors has been limited. We incorporated 4-1BB into the anti-GD2 CAR-T cells to test their cytotoxicity in melanoma in vitro and in vivo. Moreover, we reported the expression of ganglioside GD2 in non-Caucasian melanoma populations for the first time, thus providing a basis for future clinical research.

Methods

This study included tumor samples from 288 melanoma patients at the Peking University Cancer Hospital & Institute. Clinical data were collected. Immunohistochemical assays using antibodies against ganglioside GD2 were performed on formalin-fixed, paraffin-embedded specimens. The ability of ganglioside GD2 CAR-T cells to kill ganglioside GD2+ melanoma cells was evaluated in vitro and in a patient-derived xenograft (PDX) model.

Results

Among the 288 samples, 49.3% of cases (142/288) demonstrated positive staining with ganglioside GD2. The median survival time in patients exhibiting ganglioside GD2 expression was significantly shorter than that in patients without ganglioside GD2 expression (31 vs. 47.1 months, P < 0.001). In the present study, CAR was constructed using a GD2-specific scFv (14.G2a), T cell receptor CD3ζ chain, and the CD137 (4-1BB) costimulatory motif. In addition, the GD2.BBζ CAR-T cells demonstrated specific lysis of ganglioside GD2-expressing melanoma cells in vitro. In two PDX models, mice that received intravenous or local intratumor injections of GD2.BBζ CAR-T cells experienced rapid tumor regression.

Conclusions

These data demonstrate that the rate of GD2 expression in Chinese patients is 49.3%. GD2.BBζ CAR-T cells can both efficiently lyse melanoma in a GD2-specific manner and release Th1 cytokines in an antigen-dependent manner in vitro and in vivo. Anti-GD2/4-1BB CAR-T cells represent a clinically appealing treatment strategy for Chinese melanoma patients exhibiting GD2 expression and provide a basis for future studies of the clinical application of immunotherapy for melanoma.

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Zusatzmaterial
Additional file 1: Figure S1. Structure of the viral vector. (TIFF 3119 kb)
13045_2017_548_MOESM1_ESM.tif
Additional file 2: Figure S2. (A) Staining of WM-266-4 (GD2+) and 293T(GD2-). (B) Representative photomicrograph of 20 melanoma cases. (TIFF 21902 kb)
13045_2017_548_MOESM2_ESM.tif
Additional file 3: Figure S3. Expression of MCSP in primary melanoma cell lines. (TIFF 1807 kb)
13045_2017_548_MOESM3_ESM.tif
Additional file 4: Figure S4. Th2 cytokine release of GD2/CAR-T cells. Non-transduced T cells and GD2.BBζ CAR-T cells were co-cultured (ratio of T lymphocytes:tumor cells of 20:1) with four different cell lines that were GD2-negative (293T) or were 27.4% GD2-positive (GAK) and were 47.3% GD2-positive (HMV-II) or exhibited high (WM-266-4) levels of GD2-positive cells. Culture supernatant was collected 24 h later, and the production of IL-4, IL-5, and IL-10 were measured using a CBA assay. The results are presented as the mean and SD from experiments that were performed in triplicate. *P < 0.05 by Student’s t test. (TIFF 412 kb)
13045_2017_548_MOESM4_ESM.tif
Additional file 5: Figure S5. Image of a representative tumor in the PDX models in which GD2.BBζ CAR-T cells inhibited the growth of GD2-expressing melanoma cells. Group A, PBS (i.v.); group B, non-transduced T cells (i.v.); group C, non-transduced T cells (i.t.); group D, GD2.BBζ CAR-T cells (i.v.); and group E, GD2.BBζ CAR cells (i.t.). (TIFF 8545 kb)
13045_2017_548_MOESM5_ESM.tif
Literatur
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