A phase I trial of single-agent reolysin in patients with relapsed multiple myeloma
Reolysin, a proprietary isolate of reovirus type III dearing, enters and preferentially induces apoptosis of malignant cells. RAS pathway activation has been associated with more efficient reoviral infectivity and enhanced oncolysis. Reovirus is currently in advanced solid tumor phase I-II trials; n...
Gespeichert in:
| Veröffentlicht in: | Clinical cancer research 2014-12, Vol.20 (23), p.5946-5955 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 5955 |
|---|---|
| container_issue | 23 |
| container_start_page | 5946 |
| container_title | Clinical cancer research |
| container_volume | 20 |
| creator | Sborov, Douglas W Nuovo, Gerard J Stiff, Andrew Mace, Thomas Lesinski, Gregory B Benson, Jr, Don M Efebera, Yvonne A Rosko, Ashley E Pichiorri, Flavia Grever, Michael R Hofmeister, Craig C |
| description | Reolysin, a proprietary isolate of reovirus type III dearing, enters and preferentially induces apoptosis of malignant cells. RAS pathway activation has been associated with more efficient reoviral infectivity and enhanced oncolysis. Reovirus is currently in advanced solid tumor phase I-II trials; no clinical trials have been conducted in patients with hematologic malignancies.
A phase I trial treated 12 relapsed myeloma patients at two dose levels. Reolysin was infused daily for 5 days every 28 days. Bone marrow specimens were examined by in situ-based hybridization (ISH) for CD138, p38, caspase-3, reoviral RNA, and capsid protein at screening and cycle 1 day 8. Junctional adhesion molecule 1 (JAM-1) and cancer upregulated gene 2 (CUG2) were evaluated in patient samples and multiple myeloma cell lines. Neutralizing anti-reovirus antibody assay was performed weekly during cycle 1.
There were no dose-limiting toxicities, patients reached the 3 × 10(10) TCID50 daily on days 1 to 5 dose level, and grade 3 laboratory toxicities included neutropenia, thrombocytopenia, and hypophosphatemia. ISH demonstrated reoviral genome confined in multiple myeloma cells. Reoviral capsid protein and caspase-3 were rarely identified within reoviral RNA-positive cells. The longest durations of stable disease were 4, 5, and 8 months.
Treatment with single-agent Reolysin was well tolerated and associated with avid reoviral RNA myeloma cell entry but only minimal intracellular reoviral protein production within multiple myeloma cells. Our data support that in multiple myeloma cells, Reolysin-induced oncolysis requires combination therapy, similar to other cancers. |
| doi_str_mv | 10.1158/1078-0432.CCR-14-1404 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1808711119</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1808711119</sourcerecordid><originalsourceid>FETCH-LOGICAL-c389t-b3b4a8834f0ccc333d35d5e9b2c04ac91a3007165b368eba435fd25d6f58f75b3</originalsourceid><addsrcrecordid>eNqFkF1LwzAUhoMobk5_gpJLbzqTJmmTy1H8GAwEP65Dmp5ulXStTYv035uyzVsPB054874n4UHolpIlpUI-UJLKiHAWL7PsLaI8NOFnaE6FSCMWJ-I8nE-eGbry_osQyinhl2gWi1hxRdkcva9wuzMe8Br3XWUcbkrsq_3WQWS2sO9xB40bg4JDt6avgubxT9Xvwo0zrYcC14Prq9YBrkdwTW2u0UVpnIeb41ygz6fHj-wl2rw-r7PVJrJMqj7KWc6NlIyXxFrLGCuYKASoPLaEG6uoYYSkNBE5SyTkhjNRFrEoklLIMg3qAt0f9rZd8z2A73VdeQvOmT00g9dUEpnSUOp_axIrlRARfrFA4mC1XeN9B6Vuu6o23agp0RN6PWHVE1Yd0GvK9YQ-5O6OTwx5DcVf6sSa_QL1Z37A</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1629960533</pqid></control><display><type>article</type><title>A phase I trial of single-agent reolysin in patients with relapsed multiple myeloma</title><source>MEDLINE</source><source>American Association for Cancer Research</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Alma/SFX Local Collection</source><creator>Sborov, Douglas W ; Nuovo, Gerard J ; Stiff, Andrew ; Mace, Thomas ; Lesinski, Gregory B ; Benson, Jr, Don M ; Efebera, Yvonne A ; Rosko, Ashley E ; Pichiorri, Flavia ; Grever, Michael R ; Hofmeister, Craig C</creator><creatorcontrib>Sborov, Douglas W ; Nuovo, Gerard J ; Stiff, Andrew ; Mace, Thomas ; Lesinski, Gregory B ; Benson, Jr, Don M ; Efebera, Yvonne A ; Rosko, Ashley E ; Pichiorri, Flavia ; Grever, Michael R ; Hofmeister, Craig C</creatorcontrib><description>Reolysin, a proprietary isolate of reovirus type III dearing, enters and preferentially induces apoptosis of malignant cells. RAS pathway activation has been associated with more efficient reoviral infectivity and enhanced oncolysis. Reovirus is currently in advanced solid tumor phase I-II trials; no clinical trials have been conducted in patients with hematologic malignancies.
A phase I trial treated 12 relapsed myeloma patients at two dose levels. Reolysin was infused daily for 5 days every 28 days. Bone marrow specimens were examined by in situ-based hybridization (ISH) for CD138, p38, caspase-3, reoviral RNA, and capsid protein at screening and cycle 1 day 8. Junctional adhesion molecule 1 (JAM-1) and cancer upregulated gene 2 (CUG2) were evaluated in patient samples and multiple myeloma cell lines. Neutralizing anti-reovirus antibody assay was performed weekly during cycle 1.
There were no dose-limiting toxicities, patients reached the 3 × 10(10) TCID50 daily on days 1 to 5 dose level, and grade 3 laboratory toxicities included neutropenia, thrombocytopenia, and hypophosphatemia. ISH demonstrated reoviral genome confined in multiple myeloma cells. Reoviral capsid protein and caspase-3 were rarely identified within reoviral RNA-positive cells. The longest durations of stable disease were 4, 5, and 8 months.
Treatment with single-agent Reolysin was well tolerated and associated with avid reoviral RNA myeloma cell entry but only minimal intracellular reoviral protein production within multiple myeloma cells. Our data support that in multiple myeloma cells, Reolysin-induced oncolysis requires combination therapy, similar to other cancers.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.CCR-14-1404</identifier><identifier>PMID: 25294913</identifier><language>eng</language><publisher>United States</publisher><subject>Aged ; Antibodies, Viral - immunology ; Biomarkers ; Cell Adhesion Molecules - metabolism ; Cell Line, Tumor ; Chromosomal Proteins, Non-Histone - metabolism ; Female ; Gene Expression ; Humans ; Male ; Middle Aged ; Multiple Myeloma - etiology ; Multiple Myeloma - pathology ; Multiple Myeloma - therapy ; Neoplasm Staging ; Oncolytic Virotherapy - adverse effects ; Oncolytic Viruses - genetics ; Oncolytic Viruses - immunology ; Receptors, Cell Surface - metabolism ; Recurrence ; Reoviridae ; Reovirus ; Retroviridae ; RNA, Viral ; Treatment Outcome ; Viral Proteins - genetics</subject><ispartof>Clinical cancer research, 2014-12, Vol.20 (23), p.5946-5955</ispartof><rights>2014 American Association for Cancer Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c389t-b3b4a8834f0ccc333d35d5e9b2c04ac91a3007165b368eba435fd25d6f58f75b3</citedby><cites>FETCH-LOGICAL-c389t-b3b4a8834f0ccc333d35d5e9b2c04ac91a3007165b368eba435fd25d6f58f75b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3343,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25294913$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sborov, Douglas W</creatorcontrib><creatorcontrib>Nuovo, Gerard J</creatorcontrib><creatorcontrib>Stiff, Andrew</creatorcontrib><creatorcontrib>Mace, Thomas</creatorcontrib><creatorcontrib>Lesinski, Gregory B</creatorcontrib><creatorcontrib>Benson, Jr, Don M</creatorcontrib><creatorcontrib>Efebera, Yvonne A</creatorcontrib><creatorcontrib>Rosko, Ashley E</creatorcontrib><creatorcontrib>Pichiorri, Flavia</creatorcontrib><creatorcontrib>Grever, Michael R</creatorcontrib><creatorcontrib>Hofmeister, Craig C</creatorcontrib><title>A phase I trial of single-agent reolysin in patients with relapsed multiple myeloma</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>Reolysin, a proprietary isolate of reovirus type III dearing, enters and preferentially induces apoptosis of malignant cells. RAS pathway activation has been associated with more efficient reoviral infectivity and enhanced oncolysis. Reovirus is currently in advanced solid tumor phase I-II trials; no clinical trials have been conducted in patients with hematologic malignancies.
A phase I trial treated 12 relapsed myeloma patients at two dose levels. Reolysin was infused daily for 5 days every 28 days. Bone marrow specimens were examined by in situ-based hybridization (ISH) for CD138, p38, caspase-3, reoviral RNA, and capsid protein at screening and cycle 1 day 8. Junctional adhesion molecule 1 (JAM-1) and cancer upregulated gene 2 (CUG2) were evaluated in patient samples and multiple myeloma cell lines. Neutralizing anti-reovirus antibody assay was performed weekly during cycle 1.
There were no dose-limiting toxicities, patients reached the 3 × 10(10) TCID50 daily on days 1 to 5 dose level, and grade 3 laboratory toxicities included neutropenia, thrombocytopenia, and hypophosphatemia. ISH demonstrated reoviral genome confined in multiple myeloma cells. Reoviral capsid protein and caspase-3 were rarely identified within reoviral RNA-positive cells. The longest durations of stable disease were 4, 5, and 8 months.
Treatment with single-agent Reolysin was well tolerated and associated with avid reoviral RNA myeloma cell entry but only minimal intracellular reoviral protein production within multiple myeloma cells. Our data support that in multiple myeloma cells, Reolysin-induced oncolysis requires combination therapy, similar to other cancers.</description><subject>Aged</subject><subject>Antibodies, Viral - immunology</subject><subject>Biomarkers</subject><subject>Cell Adhesion Molecules - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Chromosomal Proteins, Non-Histone - metabolism</subject><subject>Female</subject><subject>Gene Expression</subject><subject>Humans</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Multiple Myeloma - etiology</subject><subject>Multiple Myeloma - pathology</subject><subject>Multiple Myeloma - therapy</subject><subject>Neoplasm Staging</subject><subject>Oncolytic Virotherapy - adverse effects</subject><subject>Oncolytic Viruses - genetics</subject><subject>Oncolytic Viruses - immunology</subject><subject>Receptors, Cell Surface - metabolism</subject><subject>Recurrence</subject><subject>Reoviridae</subject><subject>Reovirus</subject><subject>Retroviridae</subject><subject>RNA, Viral</subject><subject>Treatment Outcome</subject><subject>Viral Proteins - genetics</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkF1LwzAUhoMobk5_gpJLbzqTJmmTy1H8GAwEP65Dmp5ulXStTYv035uyzVsPB054874n4UHolpIlpUI-UJLKiHAWL7PsLaI8NOFnaE6FSCMWJ-I8nE-eGbry_osQyinhl2gWi1hxRdkcva9wuzMe8Br3XWUcbkrsq_3WQWS2sO9xB40bg4JDt6avgubxT9Xvwo0zrYcC14Prq9YBrkdwTW2u0UVpnIeb41ygz6fHj-wl2rw-r7PVJrJMqj7KWc6NlIyXxFrLGCuYKASoPLaEG6uoYYSkNBE5SyTkhjNRFrEoklLIMg3qAt0f9rZd8z2A73VdeQvOmT00g9dUEpnSUOp_axIrlRARfrFA4mC1XeN9B6Vuu6o23agp0RN6PWHVE1Yd0GvK9YQ-5O6OTwx5DcVf6sSa_QL1Z37A</recordid><startdate>20141201</startdate><enddate>20141201</enddate><creator>Sborov, Douglas W</creator><creator>Nuovo, Gerard J</creator><creator>Stiff, Andrew</creator><creator>Mace, Thomas</creator><creator>Lesinski, Gregory B</creator><creator>Benson, Jr, Don M</creator><creator>Efebera, Yvonne A</creator><creator>Rosko, Ashley E</creator><creator>Pichiorri, Flavia</creator><creator>Grever, Michael R</creator><creator>Hofmeister, Craig C</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7QO</scope><scope>7T5</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope></search><sort><creationdate>20141201</creationdate><title>A phase I trial of single-agent reolysin in patients with relapsed multiple myeloma</title><author>Sborov, Douglas W ; Nuovo, Gerard J ; Stiff, Andrew ; Mace, Thomas ; Lesinski, Gregory B ; Benson, Jr, Don M ; Efebera, Yvonne A ; Rosko, Ashley E ; Pichiorri, Flavia ; Grever, Michael R ; Hofmeister, Craig C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c389t-b3b4a8834f0ccc333d35d5e9b2c04ac91a3007165b368eba435fd25d6f58f75b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Aged</topic><topic>Antibodies, Viral - immunology</topic><topic>Biomarkers</topic><topic>Cell Adhesion Molecules - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Chromosomal Proteins, Non-Histone - metabolism</topic><topic>Female</topic><topic>Gene Expression</topic><topic>Humans</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Multiple Myeloma - etiology</topic><topic>Multiple Myeloma - pathology</topic><topic>Multiple Myeloma - therapy</topic><topic>Neoplasm Staging</topic><topic>Oncolytic Virotherapy - adverse effects</topic><topic>Oncolytic Viruses - genetics</topic><topic>Oncolytic Viruses - immunology</topic><topic>Receptors, Cell Surface - metabolism</topic><topic>Recurrence</topic><topic>Reoviridae</topic><topic>Reovirus</topic><topic>Retroviridae</topic><topic>RNA, Viral</topic><topic>Treatment Outcome</topic><topic>Viral Proteins - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sborov, Douglas W</creatorcontrib><creatorcontrib>Nuovo, Gerard J</creatorcontrib><creatorcontrib>Stiff, Andrew</creatorcontrib><creatorcontrib>Mace, Thomas</creatorcontrib><creatorcontrib>Lesinski, Gregory B</creatorcontrib><creatorcontrib>Benson, Jr, Don M</creatorcontrib><creatorcontrib>Efebera, Yvonne A</creatorcontrib><creatorcontrib>Rosko, Ashley E</creatorcontrib><creatorcontrib>Pichiorri, Flavia</creatorcontrib><creatorcontrib>Grever, Michael R</creatorcontrib><creatorcontrib>Hofmeister, Craig C</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Biotechnology Research Abstracts</collection><collection>Immunology Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sborov, Douglas W</au><au>Nuovo, Gerard J</au><au>Stiff, Andrew</au><au>Mace, Thomas</au><au>Lesinski, Gregory B</au><au>Benson, Jr, Don M</au><au>Efebera, Yvonne A</au><au>Rosko, Ashley E</au><au>Pichiorri, Flavia</au><au>Grever, Michael R</au><au>Hofmeister, Craig C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A phase I trial of single-agent reolysin in patients with relapsed multiple myeloma</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2014-12-01</date><risdate>2014</risdate><volume>20</volume><issue>23</issue><spage>5946</spage><epage>5955</epage><pages>5946-5955</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>Reolysin, a proprietary isolate of reovirus type III dearing, enters and preferentially induces apoptosis of malignant cells. RAS pathway activation has been associated with more efficient reoviral infectivity and enhanced oncolysis. Reovirus is currently in advanced solid tumor phase I-II trials; no clinical trials have been conducted in patients with hematologic malignancies.
A phase I trial treated 12 relapsed myeloma patients at two dose levels. Reolysin was infused daily for 5 days every 28 days. Bone marrow specimens were examined by in situ-based hybridization (ISH) for CD138, p38, caspase-3, reoviral RNA, and capsid protein at screening and cycle 1 day 8. Junctional adhesion molecule 1 (JAM-1) and cancer upregulated gene 2 (CUG2) were evaluated in patient samples and multiple myeloma cell lines. Neutralizing anti-reovirus antibody assay was performed weekly during cycle 1.
There were no dose-limiting toxicities, patients reached the 3 × 10(10) TCID50 daily on days 1 to 5 dose level, and grade 3 laboratory toxicities included neutropenia, thrombocytopenia, and hypophosphatemia. ISH demonstrated reoviral genome confined in multiple myeloma cells. Reoviral capsid protein and caspase-3 were rarely identified within reoviral RNA-positive cells. The longest durations of stable disease were 4, 5, and 8 months.
Treatment with single-agent Reolysin was well tolerated and associated with avid reoviral RNA myeloma cell entry but only minimal intracellular reoviral protein production within multiple myeloma cells. Our data support that in multiple myeloma cells, Reolysin-induced oncolysis requires combination therapy, similar to other cancers.</abstract><cop>United States</cop><pmid>25294913</pmid><doi>10.1158/1078-0432.CCR-14-1404</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1078-0432 |
| ispartof | Clinical cancer research, 2014-12, Vol.20 (23), p.5946-5955 |
| issn | 1078-0432 1557-3265 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1808711119 |
| source | MEDLINE; American Association for Cancer Research; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Aged Antibodies, Viral - immunology Biomarkers Cell Adhesion Molecules - metabolism Cell Line, Tumor Chromosomal Proteins, Non-Histone - metabolism Female Gene Expression Humans Male Middle Aged Multiple Myeloma - etiology Multiple Myeloma - pathology Multiple Myeloma - therapy Neoplasm Staging Oncolytic Virotherapy - adverse effects Oncolytic Viruses - genetics Oncolytic Viruses - immunology Receptors, Cell Surface - metabolism Recurrence Reoviridae Reovirus Retroviridae RNA, Viral Treatment Outcome Viral Proteins - genetics |
| title | A phase I trial of single-agent reolysin in patients with relapsed multiple myeloma |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-05T08%3A12%3A18IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20phase%20I%20trial%20of%20single-agent%20reolysin%20in%20patients%20with%20relapsed%20multiple%20myeloma&rft.jtitle=Clinical%20cancer%20research&rft.au=Sborov,%20Douglas%20W&rft.date=2014-12-01&rft.volume=20&rft.issue=23&rft.spage=5946&rft.epage=5955&rft.pages=5946-5955&rft.issn=1078-0432&rft.eissn=1557-3265&rft_id=info:doi/10.1158/1078-0432.CCR-14-1404&rft_dat=%3Cproquest_cross%3E1808711119%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1629960533&rft_id=info:pmid/25294913&rfr_iscdi=true |