Dataset Information

H3.3K27M HLA-A2 is not an effective immunotherapy target for diffuse midline glioma

ABSTRACT: The study investigated presentation of HLA A2 restricted H3.3K27M neopeptide using immunopeptidomics followed by DDA and/or targeted multiple monitoring reaction (MRM).

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Kirti Pandey

LAB HEAD: Anthony Wayne Purcell

PROVIDER: PXD038371 | Pride | 2023-10-24

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20180805_SR_KP_C1RA3-mutHistone_heavy_spike_GAPA3_pool1.mgf	Mgf
	20180805_SR_KP_C1RA3-mutHistone_heavy_spike_GAPA3_pool1.raw	Raw
	20180805_SR_KP_C1RA3-mutHistone_heavy_spike_GAPA3_pool2.mgf	Mgf
	20180805_SR_KP_C1RA3-mutHistone_heavy_spike_GAPA3_pool2.raw	Raw
	20180805_SR_KP_C1RA3-mutHistone_heavy_spike_GAPA3_pool3.mgf	Mgf

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Publications

Endogenous H3.3K27M derived peptide restricted to HLA-A∗02:01 is insufficient for immune-targeting in diffuse midline glioma.

Wang Stacie S SS Pandey Kirti K Watson Katherine A KA Abbott Rebecca C RC Mifsud Nicole A NA Gracey Fiona M FM Ramarathinam Sri H SH Cross Ryan S RS Purcell Anthony W AW Jenkins Misty R MR

Molecular therapy oncolytics 20230815

Diffuse midline glioma (DMG) is a childhood brain tumor with an extremely poor prognosis. Chimeric antigen receptor (CAR) T cell therapy has recently demonstrated some success in DMG, but there may a need to target multiple tumor-specific targets to avoid antigen escape. We developed a second-generation CAR targeting an HLA-A∗02:01 restricted histone 3K27M epitope in DMG, the target of previous peptide vaccination and T cell receptor-mimics. These CAR T cells demonstrated specific, titratable, b ...[more]

PMID: 37674626

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Project description:Background Clinical success of T cell receptor (TCR) gene therapy has previously been demonstrated for NY-ESO-1 TCR gene therapy. To increase numbers of cancer patients that can be treated with TCR gene therapy we aimed to identify a novel set of high-affinity cancer specific TCRs targeting different cancer testis (CT) antigens in prevalent HLA class I alleles. Methods In this study, we selected based on publicly available gene expression databases the most promising CT genes to target. From these selected genes we identified by HLA peptidomics the naturally processed and presented HLA class I peptides. With these peptide-HLA tetramers were generated, and by single cell sorting CT specific CD8+ T cells were selected, and expanded from the allo-HLA repertoire of healthy donors. By several functional assays high avidity CT-specific T cell clones with safe recognition pattern were selected. To evaluate the potential for clinical application in TCR gene therapy, TCRs were sequenced and transferred into peripheral blood derived CD8+ T cells. Results In total we identified, 7 novel CT-specific TCRs that effectively target MAGE-A1, MAGE-A3, MAGE-A6 and MAGE-A9 in the context of human leukocyte antigen(HLA) -A1, -A2, -A3, -B7, -B35 and -C7. TCR gene transfer into CD8⁺ T cells resulted in efficient cytokine production and cytotoxicity of variety of different tumor types without detectable cross-reactivity. In addition, major in vivo antitumor effects of MAGE-A1 specific TCR engineered CD8⁺ T cells was observed in an orthotopic xenograft model for established multiple myeloma, in which bone marrow located tumor cells were completely eradicated after T cell injection. Conclusion The identification of 7 novel CT-specific TCRs, reactive against CT antigens presented in a variety of different HLA class I alleles, allows selection of therapeutic TCRs for an increased number of cancer patients, and will improve development of personalized TCR gene therapy.