Immunotherapy of Melanoma

Bender, Carolin; Hassel, Jessica C.; Enk, Alexander H.

doi:10.1159/000446716

Cited by 14 publications

(9 citation statements)

References 71 publications

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“…In other cases, merging the immune infiltrate into one immuno-subgroup might result in opposing survival differences cancelling each other out, for example, if T cells were associated with a good prognosis and macrophages a bad prognosis. Understanding the immune heterogeneity of tumors may be key to predicting responses to immunotherapy (58,59).…”

Section: Discussionmentioning

confidence: 99%

Immune Cell Gene Signatures for Profiling the Microenvironment of Solid Tumors

Nirmal

Regan

Shih

et al. 2018

Cancer Immunology Research

177

171

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The immune composition of the tumor microenvironment regulates processes including angiogenesis, metastasis, and the response to drugs or immunotherapy. To facilitate the characterization of the immune component of tumors from transcriptomics data, a number of immune cell transcriptome signatures have been reported that are made up of lists of marker genes indicative of the presence a given immune cell population. The majority of these gene signatures have been defined through analysis of isolated blood cells. However, blood cells do not reflect the differentiation or activation state of similar cells within tissues, including tumors, and consequently markers derived from blood cells do not necessarily transfer well to tissues. To address this issue, we generated a set of immune gene signatures derived directly from tissue transcriptomics data using a network-based deconvolution approach. We define markers for seven immune cell types, collectively named ImSig, and demonstrate how these markers can be used for the quantitative estimation of the immune cell content of tumor and nontumor tissue samples. The utility of ImSig is demonstrated through the stratification of melanoma patients into subgroups of prognostic significance and the identification of immune cells with the use of single-cell RNA-sequencing data derived from tumors. Use of ImSig is facilitated by an R package (imsig). Cancer Immunol Res; 6(11); 1388-400. Ó2018 AACR.

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Section: Discussionmentioning

confidence: 99%

Immune Cell Gene Signatures for Profiling the Microenvironment of Solid Tumors

Nirmal

Regan

Shih

et al. 2018

Cancer Immunology Research

177

171

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“…1,4,24 Moreover, insufficient tumor antigen processing and presentation by DC may hamper the development of tumor-specific T cells. 25 Many therapies aiming to boost T cell responses are now in use 26,27 and CD8 T cells are the key players in anti-tumor immune responses since increased intra-tumoral infiltration of these cells was reported to correlate with a better patient outcome. 28 Vaccinations using neo-antigens are now in the focus since they could be promising in breaking immune tolerance.…”

Section: Discussionmentioning

confidence: 99%

Optimized dendritic cell vaccination induces potent CD8 T cell responses and anti-tumor effects in transgenic mouse melanoma models

et al. 2018

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Despite melanoma immunogenicity and remarkable therapeutic effects of negative immune checkpoint inhibitors, a significant fraction of patients does not respond to current treatments. This could be due to limitations in tumor immunogenicity and profound immunosuppression in the melanoma microenvironment. Moreover, insufficient tumor antigen processing and presentation by dendritic cells (DC) may hamper the development of tumor-specific T cells. Using two genetically engineered mouse melanoma models ( and transgenic mice), in which checkpoint inhibitor therapy alone is not efficacious, we performed proof-of-concept studies with an improved, multivalent DC vaccination strategy based on our recently developed genetic mRNA cancer vaccines. The expression of multiple chimeric MHC class I receptors allows a simultaneous presentation of several melanoma-associated shared antigens tyrosinase related protein (TRP)-1, tyrosinase, human glycoprotein 100 and TRP-2. The DC vaccine induced a significantly improved survival in both transgenic mouse models. Vaccinated melanoma-bearing mice displayed an increased CD8 T cell reactivity indicated by a higher IFN-γ production and an upregulation of activation marker expression along with an attenuated immunosuppressive pattern of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg). The combination of DC vaccination with ultra-low doses of paclitaxel or anti-PD-1 antibodies resulted in further prolongation of mouse survival associated with a stronger reduction of MDSC and Treg immunosuppressive phenotype. Our data suggest that an improved multivalent DC vaccine based on shared tumor antigens induces potent anti-tumor effects and could be combined with checkpoint inhibitors or targeting immunosuppressive cells to further improve their therapeutic efficiency.

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“…Regarding malignant melanoma, which still ranks high among tumors with bad prognoses [ 45 ], there are various tumor antigens that can be exploited in adoptive cell therapy. The melanosomal membrane-protein glycoprotein 100 (gp100), which is enriched in melanocytes and melanoma cells [ 46 , 47 ], can be targeted with an α/β TCR [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

RNA-transfection of γ/δ T cells with a chimeric antigen receptor or an α/β T-cell receptor: a safer alternative to genetically engineered α/β T cells for the immunotherapy of melanoma

et al. 2017

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BackgroundAdoptive T-cell therapy relying on conventional T cells transduced with T-cell receptors (TCRs) or chimeric antigen receptors (CARs) has caused substantial tumor regression in several clinical trials. However, genetically engineered T cells have been associated with serious side-effects due to off-target toxicities and massive cytokine release. To obviate these concerns, we established a protocol adaptable to GMP to expand and transiently transfect γ/δ T cells with mRNA.MethodsPBMC from healthy donors were stimulated using zoledronic-acid or OKT3 to expand γ/δ T cells and bulk T cells, respectively. Additionally, CD8+ T cells and γ/δ T cells were MACS-isolated from PBMC and expanded with OKT3. Next, these four populations were electroporated with RNA encoding a gp100/HLA-A2-specific TCR or a CAR specific for MCSP. Thereafter, receptor expression, antigen-specific cytokine secretion, specific cytotoxicity, and killing of the endogenous γ/δ T cell-target Daudi were analyzed.ResultsUsing zoledronic-acid in average 6 million of γ/δ T cells with a purity of 85% were generated from one million PBMC. MACS-isolation and OKT3-mediated expansion of γ/δ T cells yielded approximately ten times less cells. OKT3-expanded and CD8+ MACS-isolated conventional T cells behaved correspondingly similar. All employed T cells were efficiently transfected with the TCR or the CAR. Upon respective stimulation, γ/δ T cells produced IFNγ and TNF, but little IL-2 and the zoledronic-acid expanded T cells exceeded MACS-γ/δ T cells in antigen-specific cytokine secretion. While the cytokine production of γ/δ T cells was in general lower than that of conventional T cells, specific cytotoxicity against melanoma cell lines was similar. In contrast to OKT3-expanded and MACS-CD8+ T cells, mock-electroporated γ/δ T cells also lysed tumor cells reflecting the γ/δ T cell-intrinsic anti-tumor activity. After transfection, γ/δ T cells were still able to kill MHC-deficient Daudi cells.ConclusionWe present a protocol adaptable to GMP for the expansion of γ/δ T cells and their subsequent RNA-transfection with tumor-specific TCRs or CARs. Given the transient receptor expression, the reduced cytokine release, and the equivalent cytotoxicity, these γ/δ T cells may represent a safer complementation to genetically engineered conventional T cells in the immunotherapy of melanoma (Exper Dermatol 26: 157, 2017, J Investig Dermatol 136: A173, 2016).Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3539-3) contains supplementary material, which is available to authorized users.

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Immunotherapy of Melanoma

Cited by 14 publications

References 71 publications

Immune Cell Gene Signatures for Profiling the Microenvironment of Solid Tumors

Immune Cell Gene Signatures for Profiling the Microenvironment of Solid Tumors

Optimized dendritic cell vaccination induces potent CD8 T cell responses and anti-tumor effects in transgenic mouse melanoma models

RNA-transfection of γ/δ T cells with a chimeric antigen receptor or an α/β T-cell receptor: a safer alternative to genetically engineered α/β T cells for the immunotherapy of melanoma

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