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Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy [scRNA-seq]

ABSTRACT: Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a compelling tumor-associated cell surface antigen for therapeutic targeting in solid tumors. Here, we identified broad expression of STEAP1 relative to the established theranostic target prostate-specific membrane antigen (PSMA) in a series of lethal metastatic prostate cancers which prompted the development of a STEAP1-directed chimeric antigen receptor (CAR) T cell therapy. STEAP1 CAR T cells demonstrated reactivity in low antigen density, antitumor activity across multiple metastatic human and mouse prostate cancer models, and preliminary safety in a human STEAP1 knock-in mouse model. In human-in-mouse and mouse-in-mouse studies, STEAP1 CAR T cell therapy yielded effective tumor responses, but antigen escape was appreciated as a recurrent mechanism of treatment resistance and STEAP1 antigen loss was associated with diminished tumor antigen processing and presentation. The application of tumor-localized interleukin-12 (IL-12) therapy in the form of a collagen binding domain (CBD)-IL-12 fusion protein as an adjunct to STEAP1 CAR T cell therapy enhanced antitumor efficacy by remodeling the immunologically cold tumor microenvironment of prostate cancer and combating STEAP1 antigen escape through the engagement of host immunity and epitope spreading. In summary, we describe the extent of STEAP1 expression in treatment-refractory metastatic prostate cancer, characterize a STEAP1 CAR T cell therapy with preclinical evidence of potency and safety, and nominate a combinatorial immunotherapy strategy to overcome barriers to the efficacy of CAR T cell therapy in advanced prostate cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE214584 | GEO | 2023/03/22

REPOSITORIES: GEO

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Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy [bulk RNA-seq]

Project description:Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a compelling tumor-associated cell surface antigen for therapeutic targeting in solid tumors. Here, we identified broad expression of STEAP1 relative to the established theranostic target prostate-specific membrane antigen (PSMA) in a series of lethal metastatic prostate cancers which prompted the development of a STEAP1-directed chimeric antigen receptor (CAR) T cell therapy. STEAP1 CAR T cells demonstrated reactivity in low antigen density, antitumor activity across multiple metastatic human and mouse prostate cancer models, and preliminary safety in a human STEAP1 knock-in mouse model. In human-in-mouse and mouse-in-mouse studies, STEAP1 CAR T cell therapy yielded effective tumor responses, but antigen escape was appreciated as a recurrent mechanism of treatment resistance and STEAP1 antigen loss was associated with diminished tumor antigen processing and presentation. The application of tumor-localized interleukin-12 (IL-12) therapy in the form of a collagen binding domain (CBD)-IL-12 fusion protein as an adjunct to STEAP1 CAR T cell therapy enhanced antitumor efficacy by remodeling the immunologically cold tumor microenvironment of prostate cancer and combating STEAP1 antigen escape through the engagement of host immunity and epitope spreading. In summary, we describe the extent of STEAP1 expression in treatment-refractory metastatic prostate cancer, characterize a STEAP1 CAR T cell therapy with preclinical evidence of potency and safety, and nominate a combinatorial immunotherapy strategy to overcome barriers to the efficacy of CAR T cell therapy in advanced prostate cancer.

2023-03-22 | GSE214583 | GEO

Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy [TCR-seq]

2023-04-03 | GSE228884 | GEO

Gene expression profiles of chimeric cytokine receptor-engineered CAR-T cells

Project description:The efficacy of chimeric antigen receptor (CAR)-engineered T cell therapy is suboptimal in most of the cancer types , necessitating further improvement in their therapeutic actions. However, enhancing antitumor T cell response inevitably confers an increased risk of cytokine release syndrome associated with monocyte-derived IL-6 secretion. Thus, a novel approach to simultaneously enhance therapeutic efficacy and safety is warranted. In this study, we developed a chimeric cytokine receptor composed of the extracellular domains of GP130 and IL6RA linked to the transmembrane and cytoplasmic domain of IL-7R mutant that constitutively activate JAK-STAT pathway (G6/7R). CAR-T cells with G6/7R efficiently absorbed and degraded monocyte-derived IL-6 both in vitro and in vivo. The G6/7R-expressing CAR-T cells showed superior expansion and persistence in vivo, which resulted in durable antitumor response in multple tumor models. Our strategy can be widely applicable to CAR-T cell therapy to enhance its efficacy and safety, irrespective of the target antigen.

2024-03-24 | GSE216734 | GEO

Gene expression in Ewing tumor cell lines after STEAP1 silencing

Project description:Goal: identification of differentially expressed genes after STEAP1 silencing. Ewing tumors (ET) are characterized by oncogenic EWS/ETS translocations and early metastasis. STEAP1 is a membrane-bound channel protein of unkown function. While overexpressed in many cancers, STEAP1 expression is strongly restricted to mesenchymal stem cells, prostate and urothelium among benign tissues. Here we show that STEAP1 is a direct transcriptional target of EWS/FLI1 and critical for ET malignancy. We demonstrate that STEAP1 is most prominently expressed in ET among sarcomas and provide further evidence for the concept of STEAP1 as a universal diagnostic marker for carcinomas. Using RNA interference we determined that STEAP1 promotes cellular invasiveness and anchorage-independent growth in vitro and accelerates tumor growth and metastasis in vivo. Transcriptome and proteome analyses as well as functional studies reveal that STEAP1 contributes to the generation of reactive oxygen species that in turn regulate the levels of redox-sensitive signaling molecules and pro-metatstatic genes. In synopsis, these data illuminate the hitherto unkown oncogenic function of STEAP1 as a redox-modulator in ET and point to a potential role of STEAP1 as universal drug target for anti-cancer therapy. 6 samples (3x A673 cells; 3x SK-N-MC cells); for each cell line one sample was transfected with control non silencing siRNA and two samples with different STEAP1 siRNAs (siSTEAP1_2 and siSTEAP1_3).

2012-01-01 | E-GEOD-26422 | biostudies-arrayexpress

Quantitative Proteome Analysis reveal the involvement of STEAP1 on vesicles-mediated transport in human LNCaP prostate cancer cells

Project description:Prostate cancer (PCa) continues to be one of the most common cancers in men worldwide. The six transmembrane epithelial antigen of the prostate 1 (STEAP1) protein is overexpressed in several types of human tumours, particularly in PCa. Our research group has demonstrated that STEAP1 overexpression is associated with PCa progression and aggressiveness. Therefore, understanding the cellular and molecular mechanisms triggered by STEAP1 overexpression will provide important insights to delineate new strategies for PCa treatment. In the present work, a proteomic strategy was used to characterize the intracellular signalling pathways and the molecular targets downstream of STEAP1 in PCa cells. A label-free approach was applied using an Orbitrap LC-MS/MS system to characterize the proteome of STEAP1-knockdown PCa cells. More than 6700 proteins were identified, of which a total of 526 proteins were found differentially expressed in scramble siRNA versus STEAP1 siRNA (234 proteins up-regulated and 292 proteins down-regulated). Bioinformatics analysis allowed us to explore the mechanism through which STEAP1 exerts influence on PCa, revelling that endocytosis, RNA transport, apoptosis, aminoacyl-tRNA biosynthesis and metabolic pathways are the biological processes where STEAP1 is involved. By immunoblotting, it was confirmed that STEAP1 knockdown induced the up-regulation of cathepsin B, intersectin-1 and syntaxin 4,while it down-regulation HRas, PIK3C2A and DIS3. These finding suggested that blocking STEAP1 might be a strategy to activate apoptosis and endocytosis, and diminish cellular metabolism and intercellular communication, leading to inhibition of PCa progression.

2023-10-18 | PXD037834 | Pride

The interation of CAR-NK cell and tumor cells during the in vivo anti-tumor cell therapy

Project description:Chimeric antigen receptor (CAR) engineering of NK cells is an active area of research with early-phase clinical studies showing an excellent safety profile with encouraging clinical responses. However, the transcriptional signatures that control the fate of CAR-NK cell after infusion and their association with tumor control remain poorly understood. Here, we performed single-cell RNA sequencing (scRNA-seq) to depict the evolution of various engineered CAR-NK cells from the ex vivo infusion products to the in vivo peak phase of tumor control and finally to the relapse phase. Single cell RNA sequencing (scRNA) has revolutionized high-thoughout systems-based analysis of cellular and functional heterogeneity, and dynamic changes in the immune response during the anti-tumor immune cell therapy . The goals of this work are to compare transcriptome profiling (RNA-seq) from both engrafted tumor cells and infused CAR-NK cells over time of treatment course to evaluate the kenetic of tumor cell response and effector functional change of CAR-NK cell. Our study represents the first detailed transcriptomic analysis of using CAR-NK cell therapy aganist Raji-engrafted mouse model. Collecting samples from different time points and organs, the data analysis reported here should privide an envision of the dynamic about how tumor response to immune cell therapy of using CAR-NK cells and also how immune effector fucntion of CAR-NK cell was modulated over time during the treatment courses.

2022-05-25 | GSE190976 | GEO

An Informatic Approach to Chimeric Antigen Receptor Discovery Integrates Proteomics and Transcriptomics to Identify Novel Combinatorial Pairs

Project description:Chimeric antigen receptor (CAR) therapy targeting CD19 yielded remarkable outcomes in patients with acute lymphoblastic leukemia. To identify potential CAR targets in acute myeloid leukemia (AML), we probed the AML surfaceome for over-expressed molecules with potentially tolerable systemic expression. We integrated large transcriptomics and proteomics data sets from malignant and normal tissues, and developed an algorithm to identify potential targets expressed in leukemia stem cells, but not in normal CD34+CD38– hematopoietic cells, T cells or vital tissues. As these investigations did not uncover candidate targets with a profile as favorable as CD19, we developed a generalizable combinatorial targeting strategy fulfilling stringent efficacy and safety criteria. Our findings indicate that several target pairings hold great promise for CAR therapy of AML.

2017-10-24 | PXD007552 | Pride

Concert between cytokines and costimulatory domains to optimize chimeric antigen receptor immunotherapy in neuroblastoma model

Project description:Adoptive T cell therapy with gene-modified T cells expressing chimeric antigen receptor (CAR) is a rapidly growing field of translational medicine and recently has shown dramatic therapeutic success in the treatment of B-cell malignancies. However, challenges to achieve similar response in patients harboring solid tumour are still considerable. To achieve anti-tumor efficacy, these cells must survive, expand and persist after infusion into patients. An important lesson has been derived from clinical trials using CAR technologies: the relevance of the CAR design to enhance signaling and sustain T cell proliferation and survival. Here, we prove that third generation CARs specific for GD2 antigen incorporating CD28.4-1BB costimulatory domains improves T cell immunotherapy in a neuroblastoma (NB) pre-clinical model, as compared to a CAR with the same specificity but including CD28.OX40 costimulation. Indeed, we test the anti-tumor activity of polyclonal T cells genetically modified with third generation CAR.GD2 incorporating either CD28.4-1BB or CD28.OX40 in frame with the safety switch inducible Caspase 9 (iC9). We prove a significant in vitro and in vivo amelioration of the approach by the presence of 4.1BB signaling in terms of: 1) less T cell exhaustion, 2) lower basal T cell activation, 3) higher in vivo tumor control and 4) T cell persistence. In addition, the fine tuning of T cell culture conditions with the use of IL7 and IL15 show to be synergic with the third generation CAR.GD2 design to optimize CAR T immunotherapy for NB. Our results provide a proof-of-concept for the need to optimize not only CAR construct design but also T cell culture conditions in order to boost T cell activity in vivo.

2018-06-27 | PXD005426 | Pride

Gene expression in Ewing tumor cell lines after STEAP1 silencing

2012-01-01 | GSE26422 | GEO

c-Kit signaling potentiates CAR T-cell efficacy in solid tumors by CD28- and IL-2–independent costimulation

Project description:The limited efficacy of chimeric antigen receptor (CAR) T-cell therapy for solid tumors necessitates engineering strategies that promote functional persistence in an immunosuppressive environment. Herein, we exploit c-Kit signaling, a physiological pathway associated with stemness in hematopoietic progenitor cells (T cells lose expression of c-Kit during differentiation). CAR T cells with intracellular expression—but no cell-surface receptor expression—of the c-Kit D816V mutation (KITv) have upregulated STAT phosphorylation, antigen-activation-dependent proliferation, CD28- and IL-2–independent and IFN-γ–mediated costimulation, augmenting the cytotoxicity of first-generation CAR T cells. This translates to enhanced survival, including in TGF-β–rich and low-antigen-expressing solid tumor models. KITv CAR T cells have equivalent or better in vivo efficacy than second-generation CAR T cells and are susceptible to tyrosine kinase inhibitors (safety switch). When combined with CD28 costimulation, KITv costimulation functions as a third signal, enhancing efficacy and providing a potent approach to treat solid tumors.

2023-04-24 | GSE229026 | GEO

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