Addition of an Fc-IgG induces receptor clustering and increases the in vitro efficacy and in vivo anti-tumor properties of the thrombospondin-1 type I repeats (3TSR) in a mouse model of advanced stage ovarian cancer

Matuszewska, Kathy; Kortenaar, Simone Ten; Pereira, Madison; Santry, Lisa A.; Petrik, Duncan; Lo, Kin-Ming; Bridle, Byram W.; Wootton, Sarah K.; Lawler, Jack; Petrik, Jim

doi:10.1016/j.ygyno.2021.11.006

Cited by 15 publications

(13 citation statements)

References 53 publications

(71 reference statements)

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“…Note that a different ELISA with lower sensitivity was used to quantify 3TSR; therefore, it is possible that 3TSR was present in the serum at ng/mL quantities. Possible reasons as to why 3TSR was present in the serum at lower concentrations than Fc3TSR and Bevacizumab, and was more rapidly cleared from circulation include the fact that 3TSR is considerably smaller in size and does not contain an Fc domain, which can bind to the neonatal Fc receptor (FcRn) and facilitate recycling and protection from degradation [ 30 , 70 ]. Unexpectedly, the duration of transgene expression was markedly reduced when AAV vectors were administered to ID8 tumor bearing mice ( Figure 5 ).…”

Section: Discussionmentioning

confidence: 99%

“…However, the half-life of 3TSR is very short [ 29 ] thus daily injections are needed to induce an optimal biological effect. Advances that permit longer term expression of 3TSR, including the addition of an Fc domain, serve to increase duration of expression, but still require weekly administrations [ 30 ]. Thus, the vectorized expression of 3TSR or Fc3TSR may serve to improve this promising treatment modality [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

“…Given that 3TSR requires daily injections due to its short half-life, and because maintenance Bevacizumab treatment results in better efficacy, we hypothesized that AAV6.2FF-mediated expression of these antiangiogenic compounds would promote sustained levels in the blood without the need for daily or frequent injections and less pharmacokinetic fluctuation. Here, we tested the hypothesis that a single administration of AAV expressing Bevacizumab, 3TSR, or a modified version of 3TSR containing the Fc domain from human IgG (Fc3TSR) [ 30 ] will result in sustained serum-expression levels and extended survival in a syngeneic orthotopic mouse model of EOC. Additionally, we investigate whether administration of oncolytic avian orthoavulavirus-1 (AOaV-1) [ 55 , 56 ] in combination with the AAV therapies will serve to further increase survival in this model.…”

Section: Introductionmentioning

confidence: 99%

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AAV-Vectored Expression of the Vascular Normalizing Agents 3TSR and Fc3TSR, and the Anti-Angiogenic Bevacizumab Extends Survival in a Murine Model of End-Stage Epithelial Ovarian Carcinoma

et al. 2022

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Epithelial ovarian cancer is the deadliest gynecological malignancy. The lack of effective treatments highlights the need for novel therapeutic interventions. The aim of this study was to investigate whether sustained adeno-associated virus (AAV) vector-mediated expression of vascular normalizing agents 3TSR and Fc3TSR and the antiangiogenic monoclonal antibody, Bevacizumab, with or without oncolytic virus treatment would improve survival in an orthotopic syngeneic mouse model of epithelial ovarian carcinoma. AAV vectors were administered 40 days post-tumor implantation and combined with oncolytic avian orthoavulavirus-1 (AOaV-1) 20 days later, at the peak of AAV-transgene expression, to ascertain whether survival could be extended. Flow cytometry conducted on blood samples, taken at an acute time point post-AOaV-1 administration (36 h), revealed a significant increase in activated NK cells in the blood of all mice that received AOaV-1. T cell analysis revealed a significant increase in CD8+ tumor specific T cells in the blood of AAV-Bevacizumab+AOaV-1 treated mice compared to control mice 10 days post AOaV-1 administration. Immunohistochemical staining of primary tumors harvested from a subset of mice euthanized 90 days post tumor implantation, when mice typically have large primary tumors, secondary peritoneal lesions, and extensive ascites fluid production, revealed that AAV-3TSR, AAV-Fc3TSR+AOaV-1, or AAV-Bevacizumab+AOaV-1 treated mice had significantly more tumor-infiltrating CD8+ T cells than PBS controls. Despite AAV-mediated transgene expression waning faster in tumor-bearing mice than in non-tumor bearing mice, all three of the AAV therapies significantly extended survival compared to control mice; with AAV-Bevacizumab performing the best in this model. However, combining AAV therapies with a single dose of AOaV-1 did not lead to significant extensions in survival compared to AAV therapies on their own, suggesting that additional doses of AOaV-1 may be required to improve efficacy in this model. These results suggest that vectorizing anti-angiogenic and vascular normalizing agents is a viable therapeutic option that warrants further investigation, including optimizing combination therapies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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AAV-Vectored Expression of the Vascular Normalizing Agents 3TSR and Fc3TSR, and the Anti-Angiogenic Bevacizumab Extends Survival in a Murine Model of End-Stage Epithelial Ovarian Carcinoma

et al. 2022

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“…TSP-1 is released from the granules of activated platelets, prompting platelet aggregation and tethering [56]. In ovarian cancer, binding of the TSP-1 three type 1 repeats (3TSR) domain of TSP-1 to GPIV (CD36) normalizes the tumor vasculature and exhibits antitumor function [134]. Treating patients with 3TSR in combination with chemotherapeutics [135] or oncolytic viruses [136] can improve the efficacy of anticancer therapies.…”

Section: Interactions With Pericytesmentioning

confidence: 99%

Interactions between Platelets and Tumor Microenvironment Components in Ovarian Cancer and Their Implications for Treatment and Clinical Outcomes

Öncül

Cho

2023

Cancers

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Platelets, the primary operatives of hemostasis that contribute to blood coagulation and wound healing after blood vessel injury, are also involved in pathological conditions, including cancer. Malignancy-associated thrombosis is common in ovarian cancer patients and is associated with poor clinical outcomes. Platelets extravasate into the tumor microenvironment in ovarian cancer and interact with cancer cells and non-cancerous elements. Ovarian cancer cells also activate platelets. The communication between activated platelets, cancer cells, and the tumor microenvironment is via various platelet membrane proteins or mediators released through degranulation or the secretion of microvesicles from platelets. These interactions trigger signaling cascades in tumors that promote ovarian cancer progression, metastasis, and neoangiogenesis. This review discusses how interactions between platelets, cancer cells, cancer stem cells, stromal cells, and the extracellular matrix in the tumor microenvironment influence ovarian cancer progression. It also presents novel potential therapeutic approaches toward this gynecological cancer.

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“…Therefore, NG2/CSPG4-directed antibody conjugates are selectively internalized by NG2/CSPG4-expressing cancer cells through endocytosis [ 68 ]. Additionally, based on the selective NG2/CSPG4 upregulation observed in solid organ cancer-associated PCs in intra-blood vasculature lesions, this approach may also contribute to solid organ cancer regression via the inhibition of neoangiogenesis [ 69 ]. Furthermore, evaluation of a large panel of mAbs against human NG2/CSPG4 for the generation of single-chain NG2-CSPG4/CD3-bispecific antibodies, such as bispecific T-cell engagers (BiTEs) [ 70 ], showed that binding to the membrane proximal domain D3 of NG2-CSPG4 was more potent than that to distal domains; these observations were made on the CHO cell line that expresses small surface target antigens and is generally better lysed than cells expressing larger target antigens [ 71 ], suggesting that antigen size plays a role in determining target potency.…”

Section: Selection Of Ng2/cspg4 As a Target Antigen For The Treatment...mentioning

confidence: 99%

Immunotherapeutic Targeting of NG2/CSPG4 in Solid Organ Cancers

Zhang

et al. 2022

Vaccines

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: Neuro-glia antigen 2/chondroitin sulfate proteoglycan 4 (NG2/CSPG4, also called MCSP, HMW-MAA, MSK16, MCSPG, MEL-CSPG, or gp240) is a large cell-surface antigen and an unusual cell membrane integral glycoprotein frequently expressed on undifferentiated precursor cells in multiple solid organ cancers, including cancers of the liver, pancreas, lungs, and kidneys. It is a valuable molecule involved in cancer cell adhesion, invasion, spreading, angiogenesis, complement inhibition, and signaling. Although the biological significance underlying NG2/CSPG4 proteoglycan involvement in cancer progression needs to be better defined, based on the current evidence, NG2/CSPG4+ cells, such as pericytes (PCs, NG2+/CD146+/PDGFR-β+) and cancer stem cells (CSCs), are closely associated with the liver malignancy, hepatocellular carcinoma (HCC), pancreatic malignancy, and pancreatic ductal adenocarcinoma (PDAC) as well as poor prognoses. Importantly, with a unique method, we successfully purified NG2/CSPG4-expressing cells from human HCC and PDAC vasculature tissue blocks (by core needle biopsy). The cells appeared to be spheres that stably expanded in cultures. As such, these cells have the potential to be used as sources of target antigens. Herein, we provide new information on the possibilities of frequently selecting NG2/CSPG4 as a solid organ cancer biomarker or exploiting expressing cells such as CSCs, or the PG/chondroitin sulfate chain of NG2/CSPG4 on the cell membrane as specific antigens for the development of antibody- and vaccine-based immunotherapeutic approaches to treat these cancers.

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Addition of an Fc-IgG induces receptor clustering and increases the in vitro efficacy and in vivo anti-tumor properties of the thrombospondin-1 type I repeats (3TSR) in a mouse model of advanced stage ovarian cancer

Cited by 15 publications

References 53 publications

AAV-Vectored Expression of the Vascular Normalizing Agents 3TSR and Fc3TSR, and the Anti-Angiogenic Bevacizumab Extends Survival in a Murine Model of End-Stage Epithelial Ovarian Carcinoma

AAV-Vectored Expression of the Vascular Normalizing Agents 3TSR and Fc3TSR, and the Anti-Angiogenic Bevacizumab Extends Survival in a Murine Model of End-Stage Epithelial Ovarian Carcinoma

Interactions between Platelets and Tumor Microenvironment Components in Ovarian Cancer and Their Implications for Treatment and Clinical Outcomes

Immunotherapeutic Targeting of NG2/CSPG4 in Solid Organ Cancers

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