PRL3-zumab as an immunotherapy to inhibit tumors expressing PRL3 oncoprotein.
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ABSTRACT:
SUBMITTER: Thura M
PROVIDER: S-EPMC6554295 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Phosphatase of regenerating liver 3 (PRL3) is a specific tumor antigen overexpressed in a broad range of adult cancer types. However, its physiological expression in pediatric embryonal and mesenchymal tumors and its association with clinical outcomes in children is unknown. We sought to profile the expression of PRL3 in pediatric tumors in relation to survival outcomes, expression of angiogenesis markers, and G-protein-coupled receptor (GPCR)-mitogen-activated protein kinase (MAPK) signaling targets. PRL3-zumab, a first-in-class humanized antibody, was administered in a dose escalation schedule in a first-in-child clinical trial to study toxicity, pharmacokinetics, and clinical outcomes. Among 64 pediatric tumors, PRL3 was most frequently expressed in neuroblastoma (100%), rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcomas (71%), and renal sarcomas (60%) but absent in paired normal tissues. PRL3 was expressed in 75% of relapsed tumors and associated with shorter median event-free survival. Microarray profiling of PRL3-positive tumors showed elevation of angiogenin, TIMP1 and TIMP2, and GPCR-MAPK signaling proteins that commonly interacted with PRL3. The first use of PRL3-zumab in a pediatric patient saw no adverse events. A 28.6% reduction in maximum target lesion diameter was achieved when PRL3-zumab was administered concurrently with hypofractionated radiation. These findings support wider exploration of PRL3 expression in embryonal and mesenchymal tumors and further clinical application of PRL3-zumab in pediatric patients.
| S-EPMC10477756 | biostudies-literature
Project description:Phosphatase of Regenerating Liver-3 (PRL3) was discovered in 1998 and was subsequently found to be correlated with cancer progression and metastasis in 2001. Extensive research in the past two decades has produced significant findings on PRL3-mediated cancer signaling and functions, as well as its clinical relevance in diverse types of cancer. PRL3 has been established to play a role in many cancer-related functions, including but not limited to metastasis, proliferation, and angiogenesis. Importantly, the tumor-specific expression of PRL3 protein in multiple cancer types has made it an attractive therapeutic target. Much effort has been made in developing PRL3-targeted therapy with small chemical inhibitors against intracellular PRL3, and notably, the development of PRL3-zumab as a novel cancer immunotherapy against PRL3. In this review, we summarize the current understanding of the role of PRL3 in cancer-related cellular functions, its prognostic value, as well as perspectives on PRL3 as a target for unconventional immunotherapy in the clinic with PRL3-zumab.
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Project description:We report the use of 4sU-seq to determine the role of PRL3 in transcriptional processivity in human melanoma cells overexpressing either PRL3 or empty vector control. Genome-wide analysis of read coverage across length of equalised genes revealed a distinct accumulation of transcripts towards the 5’ end in PRL3 overexpressing cells. Furthermore, we identify the genes that were enriched with 5’ transcripts in the PRL3 expressing cells by comparing the intronic read counts (normalized for length) at the 5’ and 3’ end of the gene and termed this metric the transcriptional processivity ratio (TPR). Comparing the TPRs for each gene between control cells and cells expressing PRL3, we found 1745 genes that were enriched for transcripts at the 5’ end and 40 genes that were enriched at the 3’ end in the PRL3 expressing melanoma cells compared with controls. Over 62% of the genes with altered TPRs showed a significantly altered change in total RNA differential expression analysis between PRL3 cells and control cells. These data illustrate a function for PRL3 in the regulation of transcriptional processivity that is enough to substantially alter steady-state mRNA levels.
2020-07-10 | GSE127855 | GEO
Project description:Non-small cell lung cancer (NSCLC) and mesothelioma are renowned for being diagnosed at a late stage and poor prognosis. Although surgery, chemotherapy, and radiotherapy have yielded successful outcomes, the improvement on the survival rate of NSCLC and mesothelioma have been less marked. Recently, adoptive immunotherapy, particularly chimeric antigen receptor T (CAR-T) cell therapy demonstrated promise for improving the survival of acute lymphoblastic leukemia with minimum toxicity. However, its application in solid tumors still warrants in-depth investigations and multiple consistent trial results, particularly in eliminating 'off-tumor' toxicity. To explore CAR-T therapy in NSCLC and mesothelioma, second-generation CAR-T cells were constructed targeting mesothelin (MSLN), which is abundant in NSCLC and mesothelioma but is under expressed in normal tissues. The second-generation design incorporated co-stimulatory CD28 and 4-1BB signaling domains to enhance the proliferation. Following the successful analysis of CAR-T cells by flow cytometry, cytotoxicity experiments were performed using the LDH kit to verify the killing effect of CAR-T cells on target cells. Otherwise, the in vivo killing tumor activity of MSLN CAR-T cells was verified by constructing a mouse model using tumor-derived cells from patients to inoculate the mice. When the effector-to-target ratio is >0.5:1, CAR-T MSLN cells exhibited significantly higher ability to kill tumor cells than T cells. In in vivo experiments, mice whose tail vein was injected with CAR-T MSLN cells demonstrated significantly slower tumor growth. Without continuous administration, both groups became gradually synchronized in growth of tumor size, which suggests that the persistence of CAR-T cells is an important issue in preclinical studies.
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Project description:PRL3, a unique oncotarget, is specifically overexpressed in 80.6% of cancers. In 2003, we reported that PRL3 promotes cell migration, invasion, and metastasis. Herein, firstly, we show that PRL3 induces Polyploid Giant Cancer Cells (PGCCs) formation. PGCCs constitute stem cell-like pools to facilitate cell survival, chemo-resistance, and tumor relapse. The correlations between PRL3 overexpression and PGCCs attributes raised possibilities that PRL3 could be involved in PGCCs formation. Secondly, we show that PRL3+ PGCCs co-express the embryonic stem cell markers SOX2 and OCT4 and arise mainly due to incomplete cytokinesis despite extensive DNA damage. Thirdly, we reveal that PRL3+ PGCCs tolerate prolonged chemotherapy-induced genotoxic stress via suppression of the pro-apoptotic ATM DNA damage-signaling pathway. Fourthly, we demonstrated PRL3-zumab, a First-in-Class humanized antibody drug against PRL3 oncotarget, could reduce tumor relapse in 'tumor removal' animal model. Finally, we confirmed that PGCCs were enriched in relapse tumors versus primary tumors. PRL3-zumab has been approved for Phase 2 clinical trials in Singapore, US, and China to block all solid tumors. This study further showed PRL3-zumab could potentially serve an 'Adjuvant Immunotherapy' after tumor removal surgery to eliminate PRL3+ PGCC stem-like cells, preventing metastasis and relapse.
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Project description:Recent work has shown that cytotoxic T cells play a central role in immune-mediated control of cancers1-3, and monoclonal antibodies that target inhibitory receptors on T cells can induce significant clinical benefit in patients despite advanced disease4-6. However, many of the regulatory pathways that result in loss of T cell function within immunosuppressive tumors remain unknown. Here we show that such regulatory mechanisms can be systematically discovered in vivo in the tumor microenvironment. We devised a pool shRNA screening approach aimed at identifying genes that block the function of tumor-infiltrating CD8 T cells. We postulated that shRNAs targeting key inhibitors would enable robust T cell infiltration and proliferation in tumors, despite multiple inhibitory signals. Candidate shRNAs were discovered by transfer of shRNA-transduced T cells into tumor-bearing mice, followed by deep sequencing to quantify the representation of all hairpins in tumors and lymphoid organs. A subset of shRNAs induced T cell accumulation in tumors but not the spleen, demonstrating feasibility of discovering shRNAs with differential action across tissues. One of the targets was Ppp2r2d, a regulatory subunit of the family of PP2A phosphatases7. Control shRNA-transduced T cells underwent apoptosis upon recognition of melanoma cells, while Ppp2r2d shRNA-transduced T cells accumulated in tumors due to enhanced proliferation and reduced apoptosis. Ppp2r2d shRNAexpressing T cells also significantly delayed tumor growth. This in vivo approach has wide applications to dissect complex immune functions in relevant tissue microenvironments. OT-I derived T cells were transduced with shRNA's and adoptively transferred to B16 tumor bearing mice. Following incubation the T cells were purified from either tumors or spleens. The shRNA's targeted either a control gene (LacZ) or one of 5 selected genes found to regulate the presence of T cells in tumors vs in spleen
2014-03-14 | E-GEOD-53388 | biostudies-arrayexpress
Project description:Previous work from our group and others has shown that patients with breast cancer can generate a T cell response against specific human epidermal growth factor 2 (HER2) epitopes. In addition, preclinical work has shown that this T cell response can be augmented by Ag-directed mAb therapy. This study evaluated the activity and safety of a combination of dendritic cell (DC) vaccination given with mAb and cytotoxic therapy. We performed a phase I/II study using autologous DCs pulsed with two different HER2 peptides given with trastuzumab and vinorelbine to a study cohort of patients with HER2-overexpressing and a second with HER2 nonoverexpressing metastatic breast cancer. Seventeen patients with HER2-overexpressing and seven with nonoverexpressing disease were treated. Treatment was well tolerated, with one patient removed from therapy because of toxicity and no deaths. Forty-six percent of patients had stable disease after therapy, with 4% achieving a partial response and no complete responses. Immune responses were generated in the majority of patients but did not correlate with clinical response. However, in one patient, who has survived >14 y since treatment in the trial, a robust immune response was demonstrated, with 25% of her T cells specific to one of the peptides in the vaccine at the peak of her response. These data suggest that autologous DC vaccination when given with anti-HER2-directed mAb therapy and vinorelbine is safe and can induce immune responses, including significant T cell clonal expansion, in a subset of patients.
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Project description:4sU-seq of EV vs PRL3 expressing melanoma cells
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Project description:Testicular germ cell tumors (TGCTs) are malignancies with very high curative potential even in metastatic settings, mainly due to the introduction of cisplatin in the treatment of this disease. However, in a group of patients with cisplatin-refractory disease or with progressive disease despite high-dose salvage chemotherapy treatment, the prognosis is typically dismal. The triple combination of gemcitabine, oxaliplatin, and paclitaxel (GOP) has reasonable efficacy and is considered to be standard care for this group of patients. It remains to be seen, however, whether refractory TGCTs may represent a potential target for immune checkpoint inhibition. This review will focus on the rationale of the use of immunotherapy for platinum-refractory TGCTs and summarize data reporting experiences with immune checkpoint inhibitor treatment for this malignancy.
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