Abstract
BackgroundChimeric 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.MethodsThis 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.ResultsAmong 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.ConclusionsThese 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.
Highlights
Chimeric antigen receptor (CAR)-engineered T cells have demonstrated promising clinical efficacy in patients with B cell lymphoma
We use fixed pellets of WM-266-4 (GD2+) cells as positive staining tissue sections and 293T(GD2−) cells as negative tissue sections, data shown in Additional file 2: Figure S2A, representative photomicrographs of 20 melanoma cases are shown on Additional file 2: Figure S2B
The results are presented as the mean and Standard deviation (SD) from experiments that were performed in triplicate interferon-α (IFN-α), cytotoxic T cell-stimulating cytokine (CTLA-4) and programmed cell death protein 1 (PD-1) blocking antibodies [30], all of which target T cell activation
Summary
Chimeric antigen receptor (CAR)-engineered T cells have demonstrated promising clinical efficacy in patients with B cell lymphoma. Chimeric antigen receptor (CAR)-engineered T cells have demonstrated significant promising clinical efficacy in patients with hematologic malignancies [1, 2]. The complete response (CR) rate of CD19-specific CAR-T clinical trials ranges from 50 to 90% [2, 3] In a phase I study, the murine IgG3 monoclonal antibody (MoAb) 3F8, which targets ganglioside GD2, was intravenously administered to patients with neuroblastoma or melanoma. Ganglioside GD2 chimeric antigen receptor T cells have already been studied in patients with neuroblastoma in a phase I clinical trial, which indicated that anti-GD2 CAR-T cells are safe and mediate modest antitumor activity [17]
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