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Improved expansion, functionality and tumor targeting of adoptively transferred T cells with kinetically engineered IL-2

ABSTRACT: Improved expansion, functionality and tumor targeting of adoptively transferred T cells with kinetically engineered IL-2

PROVIDER: PRJNA486672 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7718911.fastq.gz	Fastqsanger.gz
	SRR7718912.fastq.gz	Fastqsanger.gz
	SRR7718913.fastq.gz	Fastqsanger.gz
	SRR7718914.fastq.gz	Fastqsanger.gz
	SRR7718915.fastq.gz	Fastqsanger.gz

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Improved expansion, functionality and tumor targeting of adoptively transferred T cells with kinetically engineered IL-2

Project description:The adoptive transfer of cancer-specific T cells in combination with high dose interleukin-2 (IL-2) is able to induce effective anti-tumor responses. However, tumors frequently relapse after an initial response and the known toxicities of IL-2 further limit the use of this therapy. NKTR-214 is a CD122-biased polyethylene glycol (PEG)-genetically engineered IL-2 designed to provide sustained signaling through the heterodimeric IL-2 receptor pathway (IL-2Rβγ) to preferentially activate and expand CD8 T and natural killer (NK) cells over T regulatory cells (Tregs) in the tumor. We report that combination of adoptive T cell transfer (ACT) and NKTR-214 markedly increases the proliferation, homing and polyfunctionality of antitumor T cells into the tumor. The treatment is well tolerated and leads to robust anti-tumor response in the aggressive B16F10 model. These results suggest that NKTR-214 could improve the efficacy of ACT protocols tested in humans.

2019-08-07 | GSE118748 | GEO

Persistence of adoptively transferred T cells with a kinetically engineered IL-2 receptor agonist.

Project description:Interleukin-2 (IL-2) is a component of most protocols of adoptive cell transfer (ACT) therapy for cancer, but is limited by short exposure and high toxicities. NKTR-214 is a kinetically-engineered IL-2 receptor βγ (IL-2Rβγ)-biased agonist consisting of IL-2 conjugated to multiple releasable polyethylene glycol chains resulting in sustained signaling through IL-2Rβγ. We report that ACT supported by NKTR-214 increases the proliferation, homing and persistence of anti-tumor T cells compared to ACT with IL-2, resulting in superior antitumor activity in a B16-F10 murine melanoma model. The use of NKTR-214 increases the number of polyfunctional T cells in murine spleens and tumors compared to IL-2, and enhances the polyfunctionality of T and NK cells in the peripheral blood of patients receiving NKTR-214 in a phase 1 trial. In conclusion, NKTR-214 may have the potential to improve the antitumor activity of ACT in humans through increased in vivo expansion and polyfunctionality of the adoptively transferred T cells.

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Combination therapy with oncolytic virus and adoptively transferred T cells or mRNA vaccine amplifies antitumor effects [scRNA-Seq]

Project description:Adoptive T-cell therapy or oncolytic virotherapy has made significant progress, but the efficacy was limited by the lack of infiltration into solid tumors when used alone. Here, an oncolytic virus (rVSV-LCMVG) was designed and combined with adoptively transferred T cells. By turning cold tumors hot, in B16 tumor-bearing mice, combination therapy showed superior antitumor effects than monotherapy, whether rVSV-LCMVG was administered intratumorally or intravenously. Combination therapy significantly increased cytokine and chemokine levels within tumors and sensitized refractory tumors by boosting T-cell recruitment, down-regulating the expression of PD1, and restoring effector-T cell function. To offer a combination therapy with greater translational value, mRNA vaccines were introduced to induce tumor-specific T cells instead of adoptively transferred T cells, and exhibited comparable amplified anti-tumor effects. This study proposed a rational combination therapy of oncolytic virus with adoptive T-cell transfer or mRNA vaccines encoding tumor-associated antigens, in terms of synergistic efficacy and mechanism.

2024-03-15 | GSE235290 | GEO

Combination therapy with oncolytic virus and adoptively transferred T cells or mRNA vaccine amplifies antitumor effects [RNA-Seq]

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CD133+PD-L1+ cancer cells confer resistance to adoptively transferred engineered macrophage-based therapy in melanoma

Project description:CD133+PD-L1+ cancer cells confer resistance to adoptively transferred engineered macrophage-based therapy in melanoma

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TLR9-activated B cells imprint adoptively transferred CD8+ T cells with potent tumor immunity and persistence

Project description:Here we report a new way to reverse the tolerant state of adoptively transferred CD8+ T cells against melanoma through ex vivo expansion with the TLR9 agonist CpG. CpG-generated T cells elicited potent immunity without co-administration of high dose IL-2 or vaccination, which are adjuvants classically required to effectively treat solid tumors. CpG-expanded T cells exhibited an IL-2RhighICOShighCD39low phenotype ex vivo and engrafted robustly in vivo. In culture, B cells were the only cell type essential for imprinting T cells with this phenotype and potent tumor immunity. CpG agonists targeting B cells, but not dendritic cells, generated CD8+ T cell products with remarkable antitumor properties. Purified B cells were sufficient to mediate the CpG-associated changes in T cells. These findings reveal a vital role for B cells in the generation of effective antitumor T cells and have immediate implications for profoundly improving immunotherapy for patients.

2022-02-22 | PXD022909 | Pride

Tumor-infiltrating, adoptively transferred BATF-overexpressing CD8 T cells analyzed via bulk RNA-seq

Project description:Tumor-infiltrating, adoptively transferred BATF-overexpressing CD8 T cells analyzed via bulk RNA-seq

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Gene expression in adoptively transferred OT-II cells isolated from mesenteric lymph nodes of control or MHCIIB-/- chimeras 5 days post-immunization with OVA and polyI:C.

Project description:To gain insight into the transcriptional program conferred to Th cells by B cells, we conducted microarray gene expression analyses of adoptively transferred OT-II cells sorted from the mesenteric lymph nodes of bone marrow chimeric control and MHCIIB-/- mice 5 days after immunization with OVA and polyI:C.

2021-11-11 | E-MTAB-11165 | biostudies-arrayexpress

CD133+PD-L1+ cancer cells confer resistance to adoptively transferred engineered macrophage-based therapy in melanoma

Project description:Adoptive transfer of genetically or nanoparticle-engineered macrophages represents a promising cell therapy modality for treatment of solid tumor. However, the therapeutic efficacy is suboptimal without achieving a complete tumor regression, and the underlying mechanism remains elusive. Here, we discover a subpopulation of cancer cells with upregulated CD133 and programmed death-ligand 1 in mouse melanoma, resistant to the phagocytosis by the transferred macrophages. Compared to the CD133-PD-L1- cancer cells, the CD133+PD-L1+ cancer cells express higher transforming growth factor-β signaling molecules to foster a resistant tumor niche, that restricts the trafficking of the transferred macrophages by stiffened extracellular matrix, and inhibits their cell-killing capability by immunosuppressive factors. The CD133+PD-L1+ cancer cells exhibit tumorigenic potential. The CD133+PD-L1+ cells are further identified in the clinically metastatic melanoma. Hyperthermia reverses the resistance of CD133+PD-L1+ cancer cells through upregulating the ‘eat me’ signal calreticulin, significantly improving the efficacy of adoptive macrophage therapy. Our findings demonstrate the mechanism of resistance to adoptive macrophage therapy, and provide a de novo strategy to counteract the resistance.

2024-11-25 | GSE282386 | GEO

Combination therapy with oncolytic virus and adoptively transferred T cells or mRNA vaccine amplifies antitumor effects

Project description:Combination therapy with oncolytic virus and adoptively transferred T cells or mRNA vaccine amplifies antitumor effects

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