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

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.Electronic supplementary materialThe online version of this article (10.1186/s13045-017-0548-2) contains supplementary material, which is available to authorized users.

TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors

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Bufotalin induces cell cycle arrest and cell apoptosis in human malignant melanoma A375 cells

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Genetically engineered T cells for cancer immunotherapy

“…The most commonly used targets for CAR-T therapy are surface antigens, such as carcinoembryonic antigen (CEA) for colorectal adenocarcinoma 175,176 , fibroblast activation protein for malignant pleural mesothelioma 177 , diganglioside GD2 for neuroblastoma 178 , glioblastoma 179 , melanoma 180 , and osteosarcoma 181 , human epidermal growth factor receptor 2 (HER2) for HER2-positive sarcoma 182 , mesothelin for pancreatic cancer 183 , IL-13 receptor α (IL-13Rα) for glioma 184 , and mutant αvβ6 integrin for pancreatic tumors 185 . TCR-engineered T cells always target the p-HLA complex.…”

“…First-generation CAR-T cells, which contain a CAR construct with only CD3ζ in the intracellular domain, showed limited antitumor efficacy in clinical trials 16,256 , mainly due to the lack of costimulatory molecules that are essential for T cell responses to antigens 257,258 . In fact, the intracellular signal transduction domain always includes the indispensable CD3ζ chain, which contains immunoreceptor tyrosine-based activation motifs (ITAMs) that function in signal transduction 259 , and one or more intracellular costimulatory molecules, such as CD28, 4-1BB (CD137), or CD27, to transmit activation signals 180,[260][261][262][263][264][265][266][267][268][269][270] . In terms of the intracellular signal domain, CARs have evolved from the first to the fourth generation.…”