Engraftment of mesothelin chimeric antigen receptor using a hybrid Sleeping Beauty/minicircle vector into NK-92MI cells for treatment of pancreatic cancer
We have previously demonstrated in vitro cytotoxicity of mesothelin-chimeric antigen receptor autologous T cells against pancreatic cancer cells using lentiviral vectors, but these vectors pose safety concerns. Here, we incorporated Sleeping Beauty and minicircle design enhancements into interleukin...
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| Veröffentlicht in: | Surgery 2019-10, Vol.166 (4), p.503-508 |
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| creator | Batchu, Ramesh B. Gruzdyn, Oksana V. Tavva, Pavan S. Kolli, Bala K. Dachepalli, Rajesh Weaver, Donald W. Gruber, Scott A. |
| description | We have previously demonstrated in vitro cytotoxicity of mesothelin-chimeric antigen receptor autologous T cells against pancreatic cancer cells using lentiviral vectors, but these vectors pose safety concerns. Here, we incorporated Sleeping Beauty and minicircle design enhancements into interleukin-2–secreting natural NK-92MI cells to eliminate both bacterial and viral components and address inhibition by the tumor microenvironment.
Parental (conventional deoxyribonucleic acid)-mesothelin-chimeric antigen receptor and minicircle-mesothelin-chimeric antigen receptor vectors were electroporated into NK-92MI cells and engraftment was visualized by immunofluorescence analysis with protein-L staining. Interferon-γ and granzyme B secretion were measured by enzyme-linked immunosorbent assay from cocultures of parental-mesothelin-chimeric antigen receptors and minicircle-mesothelin-chimeric antigen receptors with human pancreatic cancer cells, and cytotoxicity of chimeric antigen receptor NK-92MI cells was tested against three pancreatic cancer cell lines.
Cloning of mesothelin-chimeric antigen receptor Sleeping Beauty into a minicircle vector removed its bacterial backbone and reduced its size with improved electroporation efficiency. Chimeric antigen receptor engraftment, Interferon-γ and granzyme B secretion, and specific lysis against all three pancreatic cancer lines were significantly increased with minicircle-mesothelin-chimeric antigen receptor versus parental-mesothelin-chimeric antigen receptor NK-92MI cells.
We provide proof of concept that allogeneic mesothelin-chimeric antigen receptor NK-92MI cells with hybrid Sleeping Beauty and minicircle technologies provide increased engraftment and cytotoxicity in vitro with potential safety benefits when translated to the clinical arena. |
| doi_str_mv | 10.1016/j.surg.2019.05.047 |
| format | Article |
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Parental (conventional deoxyribonucleic acid)-mesothelin-chimeric antigen receptor and minicircle-mesothelin-chimeric antigen receptor vectors were electroporated into NK-92MI cells and engraftment was visualized by immunofluorescence analysis with protein-L staining. Interferon-γ and granzyme B secretion were measured by enzyme-linked immunosorbent assay from cocultures of parental-mesothelin-chimeric antigen receptors and minicircle-mesothelin-chimeric antigen receptors with human pancreatic cancer cells, and cytotoxicity of chimeric antigen receptor NK-92MI cells was tested against three pancreatic cancer cell lines.
Cloning of mesothelin-chimeric antigen receptor Sleeping Beauty into a minicircle vector removed its bacterial backbone and reduced its size with improved electroporation efficiency. Chimeric antigen receptor engraftment, Interferon-γ and granzyme B secretion, and specific lysis against all three pancreatic cancer lines were significantly increased with minicircle-mesothelin-chimeric antigen receptor versus parental-mesothelin-chimeric antigen receptor NK-92MI cells.
We provide proof of concept that allogeneic mesothelin-chimeric antigen receptor NK-92MI cells with hybrid Sleeping Beauty and minicircle technologies provide increased engraftment and cytotoxicity in vitro with potential safety benefits when translated to the clinical arena.</description><identifier>ISSN: 0039-6060</identifier><identifier>EISSN: 1532-7361</identifier><identifier>DOI: 10.1016/j.surg.2019.05.047</identifier><identifier>PMID: 31416604</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Cell Death - immunology ; Cell Line, Tumor ; Electroporation - methods ; Enzyme-Linked Immunosorbent Assay ; GPI-Linked Proteins - pharmacology ; Humans ; Immunotherapy, Adoptive - methods ; In Vitro Techniques ; Killer Cells, Natural - drug effects ; Killer Cells, Natural - immunology ; Pancreatic Neoplasms - pathology ; Pancreatic Neoplasms - therapy ; Receptors, Chimeric Antigen - immunology ; Sensitivity and Specificity ; Tumor Microenvironment</subject><ispartof>Surgery, 2019-10, Vol.166 (4), p.503-508</ispartof><rights>2019</rights><rights>Published by Elsevier Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c405t-ddebd2f1b0d258dc385b1137e99e5ac0a94a6a9c33497364a186aa5a5e2e847f3</citedby><cites>FETCH-LOGICAL-c405t-ddebd2f1b0d258dc385b1137e99e5ac0a94a6a9c33497364a186aa5a5e2e847f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0039606019303332$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31416604$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Batchu, Ramesh B.</creatorcontrib><creatorcontrib>Gruzdyn, Oksana V.</creatorcontrib><creatorcontrib>Tavva, Pavan S.</creatorcontrib><creatorcontrib>Kolli, Bala K.</creatorcontrib><creatorcontrib>Dachepalli, Rajesh</creatorcontrib><creatorcontrib>Weaver, Donald W.</creatorcontrib><creatorcontrib>Gruber, Scott A.</creatorcontrib><title>Engraftment of mesothelin chimeric antigen receptor using a hybrid Sleeping Beauty/minicircle vector into NK-92MI cells for treatment of pancreatic cancer</title><title>Surgery</title><addtitle>Surgery</addtitle><description>We have previously demonstrated in vitro cytotoxicity of mesothelin-chimeric antigen receptor autologous T cells against pancreatic cancer cells using lentiviral vectors, but these vectors pose safety concerns. Here, we incorporated Sleeping Beauty and minicircle design enhancements into interleukin-2–secreting natural NK-92MI cells to eliminate both bacterial and viral components and address inhibition by the tumor microenvironment.
Parental (conventional deoxyribonucleic acid)-mesothelin-chimeric antigen receptor and minicircle-mesothelin-chimeric antigen receptor vectors were electroporated into NK-92MI cells and engraftment was visualized by immunofluorescence analysis with protein-L staining. Interferon-γ and granzyme B secretion were measured by enzyme-linked immunosorbent assay from cocultures of parental-mesothelin-chimeric antigen receptors and minicircle-mesothelin-chimeric antigen receptors with human pancreatic cancer cells, and cytotoxicity of chimeric antigen receptor NK-92MI cells was tested against three pancreatic cancer cell lines.
Cloning of mesothelin-chimeric antigen receptor Sleeping Beauty into a minicircle vector removed its bacterial backbone and reduced its size with improved electroporation efficiency. Chimeric antigen receptor engraftment, Interferon-γ and granzyme B secretion, and specific lysis against all three pancreatic cancer lines were significantly increased with minicircle-mesothelin-chimeric antigen receptor versus parental-mesothelin-chimeric antigen receptor NK-92MI cells.
We provide proof of concept that allogeneic mesothelin-chimeric antigen receptor NK-92MI cells with hybrid Sleeping Beauty and minicircle technologies provide increased engraftment and cytotoxicity in vitro with potential safety benefits when translated to the clinical arena.</description><subject>Cell Death - immunology</subject><subject>Cell Line, Tumor</subject><subject>Electroporation - methods</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>GPI-Linked Proteins - pharmacology</subject><subject>Humans</subject><subject>Immunotherapy, Adoptive - methods</subject><subject>In Vitro Techniques</subject><subject>Killer Cells, Natural - drug effects</subject><subject>Killer Cells, Natural - immunology</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>Pancreatic Neoplasms - therapy</subject><subject>Receptors, Chimeric Antigen - immunology</subject><subject>Sensitivity and Specificity</subject><subject>Tumor Microenvironment</subject><issn>0039-6060</issn><issn>1532-7361</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UU1v1DAQtRCILoU_wAH5yCWpP5NY4gJVgYoCB-BsOfZk16vECbZTaf8KvxZHW3rk5PHovTcz7yH0mpKaEtpcHeu0xn3NCFU1kTUR7RO0o5KzquUNfYp2hHBVNaQhF-hFSkdCiBK0e44uOBW0aYjYoT83YR_NkCcIGc8DniDN-QCjD9ge_ATRW2xC9nsIOIKFJc8Rr8mHPTb4cOqjd_jHCLBsnQ9g1ny6mnzw1kc7Ar4HuxF8yDP-9qVS7OsttjCOCQ-lnSOYx8mLCXb7l4G2lBBfomeDGRO8engv0a-PNz-vP1d33z_dXr-_q6wgMlfOQe_YQHvimOyc5Z3sKeUtKAXSWGKUMI1RlnOhii_C0K4xRhoJDDrRDvwSvT3rLnH-vULKevJpW9IEmNekGWuLpy1TqkDZGWrjnFKEQS_RTyaeNCV6y0Qf9ZaJ3jLRROqSSSG9edBf-wncI-VfCAXw7gyAcuW9h6iT9VAscL5YnrWb_f_0_wLg_qCx</recordid><startdate>201910</startdate><enddate>201910</enddate><creator>Batchu, Ramesh B.</creator><creator>Gruzdyn, Oksana V.</creator><creator>Tavva, Pavan S.</creator><creator>Kolli, Bala K.</creator><creator>Dachepalli, Rajesh</creator><creator>Weaver, Donald W.</creator><creator>Gruber, Scott A.</creator><general>Elsevier Inc</general><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></search><sort><creationdate>201910</creationdate><title>Engraftment of mesothelin chimeric antigen receptor using a hybrid Sleeping Beauty/minicircle vector into NK-92MI cells for treatment of pancreatic cancer</title><author>Batchu, Ramesh B. ; Gruzdyn, Oksana V. ; Tavva, Pavan S. ; Kolli, Bala K. ; Dachepalli, Rajesh ; Weaver, Donald W. ; Gruber, Scott A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c405t-ddebd2f1b0d258dc385b1137e99e5ac0a94a6a9c33497364a186aa5a5e2e847f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Cell Death - immunology</topic><topic>Cell Line, Tumor</topic><topic>Electroporation - methods</topic><topic>Enzyme-Linked Immunosorbent Assay</topic><topic>GPI-Linked Proteins - pharmacology</topic><topic>Humans</topic><topic>Immunotherapy, Adoptive - methods</topic><topic>In Vitro Techniques</topic><topic>Killer Cells, Natural - drug effects</topic><topic>Killer Cells, Natural - immunology</topic><topic>Pancreatic Neoplasms - pathology</topic><topic>Pancreatic Neoplasms - therapy</topic><topic>Receptors, Chimeric Antigen - immunology</topic><topic>Sensitivity and Specificity</topic><topic>Tumor Microenvironment</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Batchu, Ramesh B.</creatorcontrib><creatorcontrib>Gruzdyn, Oksana V.</creatorcontrib><creatorcontrib>Tavva, Pavan S.</creatorcontrib><creatorcontrib>Kolli, Bala K.</creatorcontrib><creatorcontrib>Dachepalli, Rajesh</creatorcontrib><creatorcontrib>Weaver, Donald W.</creatorcontrib><creatorcontrib>Gruber, Scott A.</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><jtitle>Surgery</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Batchu, Ramesh B.</au><au>Gruzdyn, Oksana V.</au><au>Tavva, Pavan S.</au><au>Kolli, Bala K.</au><au>Dachepalli, Rajesh</au><au>Weaver, Donald W.</au><au>Gruber, Scott A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Engraftment of mesothelin chimeric antigen receptor using a hybrid Sleeping Beauty/minicircle vector into NK-92MI cells for treatment of pancreatic cancer</atitle><jtitle>Surgery</jtitle><addtitle>Surgery</addtitle><date>2019-10</date><risdate>2019</risdate><volume>166</volume><issue>4</issue><spage>503</spage><epage>508</epage><pages>503-508</pages><issn>0039-6060</issn><eissn>1532-7361</eissn><abstract>We have previously demonstrated in vitro cytotoxicity of mesothelin-chimeric antigen receptor autologous T cells against pancreatic cancer cells using lentiviral vectors, but these vectors pose safety concerns. Here, we incorporated Sleeping Beauty and minicircle design enhancements into interleukin-2–secreting natural NK-92MI cells to eliminate both bacterial and viral components and address inhibition by the tumor microenvironment.
Parental (conventional deoxyribonucleic acid)-mesothelin-chimeric antigen receptor and minicircle-mesothelin-chimeric antigen receptor vectors were electroporated into NK-92MI cells and engraftment was visualized by immunofluorescence analysis with protein-L staining. Interferon-γ and granzyme B secretion were measured by enzyme-linked immunosorbent assay from cocultures of parental-mesothelin-chimeric antigen receptors and minicircle-mesothelin-chimeric antigen receptors with human pancreatic cancer cells, and cytotoxicity of chimeric antigen receptor NK-92MI cells was tested against three pancreatic cancer cell lines.
Cloning of mesothelin-chimeric antigen receptor Sleeping Beauty into a minicircle vector removed its bacterial backbone and reduced its size with improved electroporation efficiency. Chimeric antigen receptor engraftment, Interferon-γ and granzyme B secretion, and specific lysis against all three pancreatic cancer lines were significantly increased with minicircle-mesothelin-chimeric antigen receptor versus parental-mesothelin-chimeric antigen receptor NK-92MI cells.
We provide proof of concept that allogeneic mesothelin-chimeric antigen receptor NK-92MI cells with hybrid Sleeping Beauty and minicircle technologies provide increased engraftment and cytotoxicity in vitro with potential safety benefits when translated to the clinical arena.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>31416604</pmid><doi>10.1016/j.surg.2019.05.047</doi><tpages>6</tpages></addata></record> |
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| ispartof | Surgery, 2019-10, Vol.166 (4), p.503-508 |
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| subjects | Cell Death - immunology Cell Line, Tumor Electroporation - methods Enzyme-Linked Immunosorbent Assay GPI-Linked Proteins - pharmacology Humans Immunotherapy, Adoptive - methods In Vitro Techniques Killer Cells, Natural - drug effects Killer Cells, Natural - immunology Pancreatic Neoplasms - pathology Pancreatic Neoplasms - therapy Receptors, Chimeric Antigen - immunology Sensitivity and Specificity Tumor Microenvironment |
| title | Engraftment of mesothelin chimeric antigen receptor using a hybrid Sleeping Beauty/minicircle vector into NK-92MI cells for treatment of pancreatic cancer |
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