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Cooperative armoring of CAR and TCR T-cells by T cell-restricted IL-15 and IL-21 universally enhances solid tumor efficacy

ABSTRACT: Cooperative armoring of CAR and TCR T-cells by T cell-restricted IL-15 and IL-21 universally enhances solid tumor efficacy

PROVIDER: PRJNA955221 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24161412.fastq.gz	Fastqsanger.gz
	SRR24161413.fastq.gz	Fastqsanger.gz
	SRR24161414.fastq.gz	Fastqsanger.gz
	SRR24161415.fastq.gz	Fastqsanger.gz
	SRR24161416.fastq.gz	Fastqsanger.gz

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Cooperative armoring of CAR and TCR T-cells by T cell-restricted IL-15 and IL-21 universally enhances solid tumor efficacy

Project description:Chimeric antigen receptor (CAR) and T-cell receptor (TCR) T-cell therapies are effective in a subset of patients with solid tumors, but new approaches are needed to enhance efficacy and universally improve patient outcomes. IL-15 and IL-21 are common cytokine-receptor gamma chain family members with distinct, pleiotropic effects on T-cells and other lymphocytes. We found that self-delivery of these cytokines by CAR or TCR T-cells prevents functional exhaustion by repeated stimulation and limits the emergence of dysfunctional natural killer (NK)-like T-cells. Across different preclinical murine solid tumor models, we observe enhanced regression with each individual cytokine but the greatest anti-tumor efficacy when T-cells are armored with both. Thus, the co-expression of membrane-tethered IL-15 and IL-21 represents a technology to enhance the resilience and function of engineered T-cells against solid tumors and could be applicable to multiple therapy platforms and diseases.

2023-08-29 | GSE229651 | GEO

A novel cooperative therapeutic regimen using gene fusion neoantigen-specific TCR-engineered T cells mediated sustained preclinical efficacy in solid tumors independent on inherent mutation profiling

Project description:Neoantigens derived from non-synonymous somatic mutations, especially gene fusion mutation, are restricted to tumor cells and thus considered ideal targets for T-cell receptor-engineering T-cells (TCR-T) immunotherapy. Adoptive transfer of neoantigen-specific TCR-T cells preferentially exhibit potent cytotoxicity preferentially to tumor cells, and has shown promising efficacy in several preclinical human cancer models. However, most neoantigens are unique to individual patient, which hinders the application of TCR-T cell therapy. In this study, we first discovered a paired / TCR repertoire, Tcr-1, that specifically targeted STY-SSX fusion neoantigen shared by almost all synovial sarcomas. Engineered T-cell expressing Tcr-1 (Tcr-T1) exhibited antigen-specific HLA-A*2402-restricted antitumoral activity against synovial sarcomas cell both in vitro and in vivo. Furthermore, to furtherly extend its application beyond synovial sarcomas, we innovatively developed a cooperative therapeutic modality, in which exogenous SYT-SSX fusion neoantigen was loaded into enzyme-responsive nanoparticles (NPs) formed by mPEG-PVGLIG-PCL copolymers (FNeo-AgNPs) for tumor targeting delivery. As expected, FNeo-AgNPs were proven of great tumor penetration, and local release. In situ modification was able to direct engineered Tcr-T1 against to other malignant gastric cancer cell line with significant antigen-specific HLA-A*2402-restricted cytotoxicity resulting in remarkable tumor regression and prolonging survival in both subcutaneous and peritoneally disseminated preclinical models, despite of their inherent mutation profiles. With these favorable data, our established cooperative therapeutic modality has a great potential for further clinical investigation, and provide a now insight for future TCR-T cell therapy development.

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Targeting KRASG12V mutations with HLA class II restricted TCR for the immunotherapy in solid tumors

Project description:Targeting KRASG12V mutations with HLA class II restricted TCR for the immunotherapy in solid tumors

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Identification of a new pathway for Th1 cell development induced by cooperative stimulation with IL-4 and TGFbeta

Project description:This SuperSeries is composed of the following subset Series: GSE36520: Identification of a new pathway for Th1 cell development induced by cooperative stimulation with IL-4 and TGFbeta [Affymetrix] GSE36554: Identification of a new pathway for Th1 cell development induced by cooperative stimulation with IL-4 and TGFbeta [Agilent] Refer to individual Series

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IL-7-primed bystander CD8 tumor-infiltrating lymphocytes optimize the antitumor efficacy of T-cell engager immunotherapy in solid tumors

Project description:Bispecific T-cell engagers (TCEs) show promising clinical efficacy in blood tumors, but their application to solid tumors with immunosuppressive environments remains challenging. Here, we show that Fc-fused IL-7 (rhIL-7-hyFc) changes the intratumoral CD8 T cell landscape, allowing TCE-immunotherapy to function effectively in solid tumors. In order to explore the transcriptomic changes induced by rhIL-7-hyFc or a combination of rhIL-7-hyFc and TCE treatment at the clonal level, we performed scRNA/TCR-seq.

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Targeting KRASG12V mutations with HLA class II restricted TCR for the immunotherapy in solid tumors

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2019-01-17 | GSE124222 | GEO

Nanostring CAR T Characterization panel comparing expression in cord blood-derived transgenic T cells cultured with IL-2 or with IL-7 and IL-15, peripheral blood-derived transgenic T cells cultured with IL-2

Project description:The purpose of the experiment was to transcriptionally characterize transgenic T cells derived from cord blood (CB) and cultured with IL-2 or IL-7 and IL-15, or from peripheral blood (PB) and cultured with IL-2. The sample replicates were generated using peripheral and cord blood mononuclear cells, obtained from healthy human donors and cord blood units that were not compliant with banking standards, respectively. T cells were then transduced with a retroviral vector encoding an HLA-DRB1*04-restricted TCR targeting the human papillomavirus oncoprotein E7.

2021-10-15 | GSE161483 | GEO

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Project description:Ely ZA, Kulstad ZJ, Gunaydin G, Addepalli S, Verzani EK, Casarrubios M, Clauser KR, Wang X, Lippincott IE, Louvet C, Schmitt T, Kapner KS, Agus MP, Hennessey CJ, Cleary JM, Hadrup SR, Klaeger S, Su J, Jaeger AM, Wolpin BM, Raghavan S, Smith EL, Greenberg PD, Aguirre AJ, Abelin JG, Carr SA, Jacks T, Freed-Pastor WA. 2025 Translation of the non-coding genome in cancer can generate cryptic peptides capable of presentation by human leukocyte antigen class I (HLA-I); however, the cancer-specificity and immunogenicity of non-canonical HLA-I-bound peptides (ncHLAp) is not fully understood. Using personalized proteogenomics coupled with high-resolution immunopeptidomics, we found that cryptic peptides are abundant in the pancreatic cancer immunopeptidome. We developed a novel translation-centric pipeline and discovered that ~30% of ncHLAp exhibit bona fide cancer-restricted translation, with a substantial subset shared among patients. Cancer-restricted ncHLAp demonstrated immunogenic potential in a highly sensitive ex vivo T cell priming platform. ncHLAp-reactive, TCR-redirected T cells (TCR-T) exhibit robust tumoricidal activity against patient-derived pancreatic cancer organoids. These findings demonstrate that dysregulated translation in pancreatic cancer can give rise to recurrent cancer-restricted ncHLAp capable of recognition by cytotoxic T cells. We anticipate future therapeutic strategies for pancreatic cancer and other solid tumors will include targeting cryptic antigens.

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