Retroviral Replicating Vector Delivery of miR-PDL1 Inhibits Immune Checkpoint PDL1 and Enhances Immune Responses In Vitro

Lin, Amy; Twitty, Christopher G.; Burnett, Ryan; Hofacre, Andrew; Mitchell, Leah; Espinoza, Fernando Lopez; Gruber, Harry E.; Jolly, Douglas J.

doi:10.1016/j.omtn.2016.11.007

Cited by 13 publications

(12 citation statements)

References 42 publications

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“…Retroviral delivery of PD-L1-targeted small hairpin RNA (shRNA) to tumor cells have been evaluated [93]. Treatment of PD-L1 expressing cancer cell lines with retroviral replication vectors (RRV) that express microRNA30-derived shRNA against PD-L1 (RRV-miRPDL1) resulted in sustained downregulation of PD-L1 expression and inhibited CD8 + T cell suppression [93]. The measured in vitro CD8 + T cell activation with RRV-miRPDL1, in trans-suppression lymphocyte assay, was similar to antibody-mediated PD-L1 blockade [93].…”

Section: Delivery Of Checkpoint Inhibitors By Viral Vectorsmentioning

confidence: 99%

“…Treatment of PD-L1 expressing cancer cell lines with retroviral replication vectors (RRV) that express microRNA30-derived shRNA against PD-L1 (RRV-miRPDL1) resulted in sustained downregulation of PD-L1 expression and inhibited CD8 + T cell suppression [93]. The measured in vitro CD8 + T cell activation with RRV-miRPDL1, in trans-suppression lymphocyte assay, was similar to antibody-mediated PD-L1 blockade [93]. The RRV-miRPDL1 was not evaluated in vivo in this study and it remains to be seen if targeted delivery of RRV-miRPDL1 to tumors may result in improved efficacy and reduced toxicities compared to systemic therapies with PD-L1 blocking antibodies.…”

Section: Delivery Of Checkpoint Inhibitors By Viral Vectorsmentioning

confidence: 99%

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Novel Delivery Systems for Checkpoint Inhibitors

et al. 2019

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Checkpoint inhibition (CPI) therapies have been proven to be powerful clinical tools in treating cancers. FDA approvals and ongoing clinical development of checkpoint inhibitors for treatment of various cancers highlight the immense potential of checkpoint inhibitors as anti-cancer therapeutics. The occurrence of immune-related adverse events, however, is a major hindrance to the efficacy and use of checkpoint inhibitors as systemic therapies in a wide range of patients. Hence, methods of sustained and tumor-targeted delivery of checkpoint inhibitors are likely to improve efficacy while also decreasing toxic side effects. In this review, we summarize the findings of the studies that evaluated methods of tumor-targeted delivery of checkpoint inhibitors, review their strengths and weaknesses, and discuss the outlook for therapeutic use of these delivery methods.

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Section: Delivery Of Checkpoint Inhibitors By Viral Vectorsmentioning

confidence: 99%

Section: Delivery Of Checkpoint Inhibitors By Viral Vectorsmentioning

confidence: 99%

Novel Delivery Systems for Checkpoint Inhibitors

et al. 2019

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“…Twenty micrograms of plasmid DNA encoding the RRVs were used for transient transfection using the calcium phosphate method as previously described [40]. The viral titers of all RRVs were determined by quantitative PCR (qPCR) and viral titers, reported in transduction units per milliliter (TU/mL) [5, 22].…”

Section: Methodsmentioning

confidence: 99%

“…For viral replication kinetics, 20 μL of collected supernatant from each time points during the course of infection were obtained to extract viral RNA and measure particle titer as described [40]. For vector genome stability, genomic DNA from each infection cycle was extracted from maximally infected U87-MG cells using the Maxwell 16 Cell DNA Purification Kit (Promega # AS1020) as described [22].…”

Section: Methodsmentioning

confidence: 99%

PD-L1 checkpoint blockade delivered by retroviral replicating vector confers anti-tumor efficacy in murine tumor models

et al. 2019

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Immune checkpoint inhibitors (CPIs) are associated with a number of immune-related adverse events and low response rates. We provide preclinical evidence for use of a retroviral replicating vector (RRV) selective to cancer cells, to deliver CPI agents that may circumvent such issues and increase efficacy. An RRV, RRV-scFv-PDL1, encoding a secreted single chain variable fragment targeting PD-L1 can effectively compete with PD-1 for PD-L1 occupancy. Cell binding assays showed trans-binding activity on 100% of cells in culture when infection was limited to 5% RRV-scFv-PDL1 infected tumor cells. Further, the ability of scFv PD-L1 to rescue PD-1/PD-L1 mediated immune suppression was demonstrated in a co-culture system consisting of human-derived immune cells and further demonstrated in several syngeneic mouse models including an intracranial tumor model. These tumor models showed that tumors infected with RRV-scFv-PD-L1 conferred robust and durable immune-mediated anti-tumor activity comparable or superior to systemically administered anti-PD-1 or anti PD-L1 monoclonal antibodies. Importantly, the nominal level of scFv-PD-L1 detected in serum is ∼50–150 fold less than reported for systemically administered therapeutic antibodies targeting immune checkpoints. These results support the concept that RRV-scFv-PDL1 CPI strategy may provide an improved safety and efficacy profile compared to systemic monoclonal antibodies of currently approved therapies.

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“…Retroviral replicating vectors (RRVs) have excellent properties in stably and selectively introducing genetic materials into cancer cells. Lin and co‐workers developed multiple configurations of RRVs to express MicroRNA 30‐based small hairpin RNA (miRshRNA) for targeting PD‐L1 . This approach has the analogical PD‐L1‐downregulated activity with anti‐PD‐L1 antibodies effectively to revitalized immune activation.…”

Section: Biomaterial‐based Strategy Integrated With Icb For Synergistmentioning

confidence: 99%

Toward Biomaterials for Enhancing Immune Checkpoint Blockade Therapy

Fan

Chen

Wang

et al. 2018

Adv Funct Materials

107

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Despite the remarkable progress in immune checkpoint blockade (ICB) therapy for cancer treatment, low objective response and immune‐related side effects (immune‐related adverse events, irAEs) limit the further development of ICBs. To address these challenges and enhance the efficiency of cancer immunotherapy, the emerging interest has focused on manipulating biomaterials to form innovational drug delivery systems that are necessary to effectively deliver immune checkpoint inhibitors. Such biomaterial‐based strategies can improve accumulation, control release, and enhance retention of checkpoint inhibitors within target locations while simultaneously reducing drug exposure for off‐target tissues, thereby optimizing both the efficacy and safety. In addition, with the assistance of biomaterials, combinations of ICB and conventional treatment strategies including chemotherapy, radiotherapy, and phototherapy are designed to further enhance the response rate of ICB. This review focuses on the latest reports on engineering biomaterials to improve the antitumor efficiency of ICB, with stress on antibody‐, gene‐, and trap protein–based immune checkpoint blockade strategies and their combinations with conventional therapies. Challenges and future trends in engineering biomaterials to modulate immune checkpoint therapy are discussed.

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Retroviral Replicating Vector Delivery of miR-PDL1 Inhibits Immune Checkpoint PDL1 and Enhances Immune Responses In Vitro

Cited by 13 publications

References 42 publications

Novel Delivery Systems for Checkpoint Inhibitors

Novel Delivery Systems for Checkpoint Inhibitors

PD-L1 checkpoint blockade delivered by retroviral replicating vector confers anti-tumor efficacy in murine tumor models

Toward Biomaterials for Enhancing Immune Checkpoint Blockade Therapy

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