In Vitro Pre-Clinical Validation of Suicide Gene Modified Anti-CD33 Redirected Chimeric Antigen Receptor T-Cells for Acute Myeloid Leukemia
Approximately fifty percent of patients with acute myeloid leukemia can be cured with current therapeutic strategies which include, standard dose chemotherapy for patients at standard risk of relapse as assessed by cytogenetic and molecular analysis, or high-dose chemotherapy with allogeneic hematop...
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| Veröffentlicht in: | PloS one 2016-12, Vol.11 (12), p.e0166891 |
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| creator | Minagawa, Kentaro Jamil, Muhammad O Al-Obaidi, Mustafa Pereboeva, Larisa Salzman, Donna Erba, Harry P Lamb, Lawrence S Bhatia, Ravi Mineishi, Shin Di Stasi, Antonio |
| description | Approximately fifty percent of patients with acute myeloid leukemia can be cured with current therapeutic strategies which include, standard dose chemotherapy for patients at standard risk of relapse as assessed by cytogenetic and molecular analysis, or high-dose chemotherapy with allogeneic hematopoietic stem cell transplant for high-risk patients. Despite allogeneic hematopoietic stem cell transplant about 25% of patients still succumb to disease relapse, therefore, novel strategies are needed to improve the outcome of patients with acute myeloid leukemia.
We developed an immunotherapeutic strategy targeting the CD33 myeloid antigen, expressed in ~ 85-90% of patients with acute myeloid leukemia, using chimeric antigen receptor redirected T-cells. Considering that administration of CAR T-cells has been associated with cytokine release syndrome and other potential off-tumor effects in patients, safety measures were here investigated and reported. We genetically modified human activated T-cells from healthy donors or patients with acute myeloid leukemia with retroviral supernatant encoding the inducible Caspase9 suicide gene, a ΔCD19 selectable marker, and a humanized third generation chimeric antigen receptor recognizing human CD33. ΔCD19 selected inducible Caspase9-CAR.CD33 T-cells had a 75±3.8% (average ± standard error of the mean) chimeric antigen receptor expression, were able to specifically lyse CD33+ targets in vitro, including freshly isolated leukemic blasts from patients, produce significant amount of tumor-necrosis-factor-alpha and interferon-gamma, express the CD107a degranulation marker, and proliferate upon antigen specific stimulation. Challenging ΔCD19 selected inducible Caspase9-CAR.CD33 T-cells with programmed-death-ligand-1 enriched leukemia blasts resulted in significant killing like observed for the programmed-death-ligand-1 negative leukemic blasts fraction. Since the administration of 10 nanomolar of a non-therapeutic dimerizer to activate the suicide gene resulted in the elimination of only 76.4±2.0% gene modified cells in vitro, we found that co-administration of the dimerizer with either the BCL-2 inhibitor ABT-199, the pan-BCL inhibitor ABT-737, or mafosfamide, resulted in an additive effect up to complete cell elimination.
This strategy could be investigated for the safety of CAR T-cell applications, and targeting CD33 could be used as a 'bridge" therapy for patients coming to allogeneic hematopoietic stem cell transplant, as a |
| doi_str_mv | 10.1371/journal.pone.0166891 |
| format | Article |
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We developed an immunotherapeutic strategy targeting the CD33 myeloid antigen, expressed in ~ 85-90% of patients with acute myeloid leukemia, using chimeric antigen receptor redirected T-cells. Considering that administration of CAR T-cells has been associated with cytokine release syndrome and other potential off-tumor effects in patients, safety measures were here investigated and reported. We genetically modified human activated T-cells from healthy donors or patients with acute myeloid leukemia with retroviral supernatant encoding the inducible Caspase9 suicide gene, a ΔCD19 selectable marker, and a humanized third generation chimeric antigen receptor recognizing human CD33. ΔCD19 selected inducible Caspase9-CAR.CD33 T-cells had a 75±3.8% (average ± standard error of the mean) chimeric antigen receptor expression, were able to specifically lyse CD33+ targets in vitro, including freshly isolated leukemic blasts from patients, produce significant amount of tumor-necrosis-factor-alpha and interferon-gamma, express the CD107a degranulation marker, and proliferate upon antigen specific stimulation. Challenging ΔCD19 selected inducible Caspase9-CAR.CD33 T-cells with programmed-death-ligand-1 enriched leukemia blasts resulted in significant killing like observed for the programmed-death-ligand-1 negative leukemic blasts fraction. Since the administration of 10 nanomolar of a non-therapeutic dimerizer to activate the suicide gene resulted in the elimination of only 76.4±2.0% gene modified cells in vitro, we found that co-administration of the dimerizer with either the BCL-2 inhibitor ABT-199, the pan-BCL inhibitor ABT-737, or mafosfamide, resulted in an additive effect up to complete cell elimination.
This strategy could be investigated for the safety of CAR T-cell applications, and targeting CD33 could be used as a 'bridge" therapy for patients coming to allogeneic hematopoietic stem cell transplant, as anti-leukemia activity from infusing CAR.CD33 T-cells has been demonstrated in an ongoing clinical trial. Albeit never performed in the clinical setting, our future plan is to investigate the utility of iC9-CAR.CD33 T-cells as part of the conditioning therapy for an allogeneic hematopoietic stem cell transplant for acute myeloid leukemia, together with other myelosuppressive agents, whilst the activation of the inducible Caspase9 suicide gene would grant elimination of the infused gene modified T-cells prior to stem cell infusion to reduce the risk of engraftment failure as the CD33 is also expressed on a proportion of the donor stem cell graft.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0166891</identifier><identifier>PMID: 27907031</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acute myelocytic leukemia ; Acute myeloid leukemia ; Antigens ; Antitumor activity ; Apoptosis ; B7-H1 Antigen - pharmacology ; Bcl-2 protein ; Biology and Life Sciences ; Biphenyl Compounds - pharmacology ; Bridged Bicyclo Compounds, Heterocyclic - pharmacology ; Cancer ; Care and treatment ; Caspase 9 - genetics ; Caspase 9 - immunology ; Cell Engineering ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Cellular Reprogramming ; Chemotherapy ; Chimeric antigen receptors ; Clinical Trials as Topic ; Cyclophosphamide - analogs & derivatives ; Cyclophosphamide - pharmacology ; Cytokines ; Cytotoxicity, Immunologic ; Degranulation ; Drug dosages ; Gene therapy ; Genetic modification ; Genetic Vectors ; Granulocytes ; Hematology ; Hematopoietic stem cells ; Humans ; Immunology ; Immunotherapy ; Inhibitors ; Interferon ; Interferon-gamma - biosynthesis ; Interferon-gamma - immunology ; Leukemia ; Leukemia, Myeloid, Acute - genetics ; Leukemia, Myeloid, Acute - immunology ; Leukemia, Myeloid, Acute - pathology ; Leukemia, Myeloid, Acute - therapy ; Ligands ; Lymphocytes ; Lymphocytes T ; Lysosomal-Associated Membrane Protein 1 - genetics ; Lysosomal-Associated Membrane Protein 1 - immunology ; Medicine and Health Sciences ; Mental health ; Myeloid Cells - drug effects ; Myeloid Cells - immunology ; Myeloid Cells - pathology ; Myeloid leukemia ; Nitrophenols - pharmacology ; Oncology ; Patients ; Piperazines - pharmacology ; Primary Cell Culture ; Receptors, Antigen, T-Cell - genetics ; Receptors, Antigen, T-Cell - immunology ; Recombinant Fusion Proteins - genetics ; Recombinant Fusion Proteins - immunology ; Research and Analysis Methods ; Risk groups ; Safety measures ; Sialic Acid Binding Ig-like Lectin 3 - antagonists & inhibitors ; Sialic Acid Binding Ig-like Lectin 3 - genetics ; Sialic Acid Binding Ig-like Lectin 3 - immunology ; Standard error ; Stem cell transplantation ; Stem cells ; Studies ; Suicidal behavior ; Suicide ; Suicide genes ; Sulfonamides - pharmacology ; T cell receptors ; T cells ; T-Lymphocytes - cytology ; T-Lymphocytes - drug effects ; T-Lymphocytes - immunology ; Transplants & implants ; Tumor Necrosis Factor-alpha - biosynthesis ; Tumor Necrosis Factor-alpha - immunology ; Tumor necrosis factor-α ; γ-Interferon</subject><ispartof>PloS one, 2016-12, Vol.11 (12), p.e0166891</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Minagawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2016 Minagawa et al 2016 Minagawa et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c725t-3388fafec0e32cd5bfa39e5bff958423c4bd0e714c218e4be858f3155d33e2b93</citedby><cites>FETCH-LOGICAL-c725t-3388fafec0e32cd5bfa39e5bff958423c4bd0e714c218e4be858f3155d33e2b93</cites><orcidid>0000-0002-7886-3514</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5132227/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5132227/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27907031$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Minagawa, Kentaro</creatorcontrib><creatorcontrib>Jamil, Muhammad O</creatorcontrib><creatorcontrib>Al-Obaidi, Mustafa</creatorcontrib><creatorcontrib>Pereboeva, Larisa</creatorcontrib><creatorcontrib>Salzman, Donna</creatorcontrib><creatorcontrib>Erba, Harry P</creatorcontrib><creatorcontrib>Lamb, Lawrence S</creatorcontrib><creatorcontrib>Bhatia, Ravi</creatorcontrib><creatorcontrib>Mineishi, Shin</creatorcontrib><creatorcontrib>Di Stasi, Antonio</creatorcontrib><title>In Vitro Pre-Clinical Validation of Suicide Gene Modified Anti-CD33 Redirected Chimeric Antigen Receptor T-Cells for Acute Myeloid Leukemia</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Approximately fifty percent of patients with acute myeloid leukemia can be cured with current therapeutic strategies which include, standard dose chemotherapy for patients at standard risk of relapse as assessed by cytogenetic and molecular analysis, or high-dose chemotherapy with allogeneic hematopoietic stem cell transplant for high-risk patients. Despite allogeneic hematopoietic stem cell transplant about 25% of patients still succumb to disease relapse, therefore, novel strategies are needed to improve the outcome of patients with acute myeloid leukemia.
We developed an immunotherapeutic strategy targeting the CD33 myeloid antigen, expressed in ~ 85-90% of patients with acute myeloid leukemia, using chimeric antigen receptor redirected T-cells. Considering that administration of CAR T-cells has been associated with cytokine release syndrome and other potential off-tumor effects in patients, safety measures were here investigated and reported. We genetically modified human activated T-cells from healthy donors or patients with acute myeloid leukemia with retroviral supernatant encoding the inducible Caspase9 suicide gene, a ΔCD19 selectable marker, and a humanized third generation chimeric antigen receptor recognizing human CD33. ΔCD19 selected inducible Caspase9-CAR.CD33 T-cells had a 75±3.8% (average ± standard error of the mean) chimeric antigen receptor expression, were able to specifically lyse CD33+ targets in vitro, including freshly isolated leukemic blasts from patients, produce significant amount of tumor-necrosis-factor-alpha and interferon-gamma, express the CD107a degranulation marker, and proliferate upon antigen specific stimulation. Challenging ΔCD19 selected inducible Caspase9-CAR.CD33 T-cells with programmed-death-ligand-1 enriched leukemia blasts resulted in significant killing like observed for the programmed-death-ligand-1 negative leukemic blasts fraction. Since the administration of 10 nanomolar of a non-therapeutic dimerizer to activate the suicide gene resulted in the elimination of only 76.4±2.0% gene modified cells in vitro, we found that co-administration of the dimerizer with either the BCL-2 inhibitor ABT-199, the pan-BCL inhibitor ABT-737, or mafosfamide, resulted in an additive effect up to complete cell elimination.
This strategy could be investigated for the safety of CAR T-cell applications, and targeting CD33 could be used as a 'bridge" therapy for patients coming to allogeneic hematopoietic stem cell transplant, as anti-leukemia activity from infusing CAR.CD33 T-cells has been demonstrated in an ongoing clinical trial. Albeit never performed in the clinical setting, our future plan is to investigate the utility of iC9-CAR.CD33 T-cells as part of the conditioning therapy for an allogeneic hematopoietic stem cell transplant for acute myeloid leukemia, together with other myelosuppressive agents, whilst the activation of the inducible Caspase9 suicide gene would grant elimination of the infused gene modified T-cells prior to stem cell infusion to reduce the risk of engraftment failure as the CD33 is also expressed on a proportion of the donor stem cell graft.</description><subject>Acute myelocytic leukemia</subject><subject>Acute myeloid leukemia</subject><subject>Antigens</subject><subject>Antitumor activity</subject><subject>Apoptosis</subject><subject>B7-H1 Antigen - pharmacology</subject><subject>Bcl-2 protein</subject><subject>Biology and Life Sciences</subject><subject>Biphenyl Compounds - pharmacology</subject><subject>Bridged Bicyclo Compounds, Heterocyclic - pharmacology</subject><subject>Cancer</subject><subject>Care and treatment</subject><subject>Caspase 9 - genetics</subject><subject>Caspase 9 - immunology</subject><subject>Cell Engineering</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Cellular Reprogramming</subject><subject>Chemotherapy</subject><subject>Chimeric antigen receptors</subject><subject>Clinical Trials as Topic</subject><subject>Cyclophosphamide - analogs & derivatives</subject><subject>Cyclophosphamide - pharmacology</subject><subject>Cytokines</subject><subject>Cytotoxicity, Immunologic</subject><subject>Degranulation</subject><subject>Drug dosages</subject><subject>Gene therapy</subject><subject>Genetic modification</subject><subject>Genetic Vectors</subject><subject>Granulocytes</subject><subject>Hematology</subject><subject>Hematopoietic stem cells</subject><subject>Humans</subject><subject>Immunology</subject><subject>Immunotherapy</subject><subject>Inhibitors</subject><subject>Interferon</subject><subject>Interferon-gamma - biosynthesis</subject><subject>Interferon-gamma - immunology</subject><subject>Leukemia</subject><subject>Leukemia, Myeloid, Acute - genetics</subject><subject>Leukemia, Myeloid, Acute - immunology</subject><subject>Leukemia, Myeloid, Acute - pathology</subject><subject>Leukemia, Myeloid, Acute - therapy</subject><subject>Ligands</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Lysosomal-Associated Membrane Protein 1 - genetics</subject><subject>Lysosomal-Associated Membrane Protein 1 - immunology</subject><subject>Medicine and Health Sciences</subject><subject>Mental health</subject><subject>Myeloid Cells - drug effects</subject><subject>Myeloid Cells - immunology</subject><subject>Myeloid Cells - pathology</subject><subject>Myeloid leukemia</subject><subject>Nitrophenols - pharmacology</subject><subject>Oncology</subject><subject>Patients</subject><subject>Piperazines - pharmacology</subject><subject>Primary Cell Culture</subject><subject>Receptors, Antigen, T-Cell - genetics</subject><subject>Receptors, Antigen, T-Cell - immunology</subject><subject>Recombinant Fusion Proteins - genetics</subject><subject>Recombinant Fusion Proteins - immunology</subject><subject>Research and Analysis Methods</subject><subject>Risk groups</subject><subject>Safety measures</subject><subject>Sialic Acid Binding Ig-like Lectin 3 - antagonists & inhibitors</subject><subject>Sialic Acid Binding Ig-like Lectin 3 - genetics</subject><subject>Sialic Acid Binding Ig-like Lectin 3 - immunology</subject><subject>Standard error</subject><subject>Stem cell transplantation</subject><subject>Stem cells</subject><subject>Studies</subject><subject>Suicidal behavior</subject><subject>Suicide</subject><subject>Suicide genes</subject><subject>Sulfonamides - pharmacology</subject><subject>T cell receptors</subject><subject>T cells</subject><subject>T-Lymphocytes - cytology</subject><subject>T-Lymphocytes - drug effects</subject><subject>T-Lymphocytes - immunology</subject><subject>Transplants & implants</subject><subject>Tumor Necrosis Factor-alpha - biosynthesis</subject><subject>Tumor Necrosis Factor-alpha - immunology</subject><subject>Tumor necrosis factor-α</subject><subject>γ-Interferon</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk81uEzEQx1cIREvhDRCshITgsGH9sbveS6UoQIkUVNSWXC3HHicuzjrYXkSfgZfG26RVgnpAPtia-c1_PGNPlr1E5QiRBn24dr3vhB1tXAejEtU1a9Gj7Bi1BBc1LsnjvfNR9iyE67KsCKvrp9kRbtqyKQk6zv5Mu3xuonf5Nw_FxJrOSGHzubBGiWhclzudX_ZGGgX5GXSQf3XKaAMqH3fRFJOPhOQXoIwHGZNxsjJr8EbeepfQJZ-ETXQ-vyomYG3IdTqPZR-T0g1YZ1Q-g_4HrI14nj3RwgZ4sdtPsu-fP11NvhSz87PpZDwrZIOrWBDCmBYaZAkES1UttCAtpE23FaOYSLpQJTSISowY0AWwimmCqkoRAnjRkpPs9VZ3Y13guz4GjhitMK0rihIx3RLKiWu-8WYt_A13wvBbg_NLLnw00gKvGsrQcAMkBF20jdCaQV3WDRVIIQFJ63SXrV-sQUnoohf2QPTQ05kVX7pfvEIEY9wkgXc7Ae9-9hAiX5sgUy9FB64f7l0zQtqmHip78w_6cHU7ailSAabTLuWVgygf0wYTVLKWJmr0AJWWSm8l06fTJtkPAt4fBCQmwu-4FH0IfHp58f_s-fyQfbvHrkDYuArO9sPvDIcg3YLSuxA86Psmo5IPM3PXDT7MDN_NTAp7tf9A90F3Q0L-AvZQESQ</recordid><startdate>20161201</startdate><enddate>20161201</enddate><creator>Minagawa, Kentaro</creator><creator>Jamil, Muhammad O</creator><creator>Al-Obaidi, Mustafa</creator><creator>Pereboeva, Larisa</creator><creator>Salzman, Donna</creator><creator>Erba, Harry P</creator><creator>Lamb, Lawrence S</creator><creator>Bhatia, Ravi</creator><creator>Mineishi, Shin</creator><creator>Di Stasi, Antonio</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-7886-3514</orcidid></search><sort><creationdate>20161201</creationdate><title>In Vitro Pre-Clinical Validation of Suicide Gene Modified Anti-CD33 Redirected Chimeric Antigen Receptor T-Cells for Acute Myeloid Leukemia</title><author>Minagawa, Kentaro ; Jamil, Muhammad O ; Al-Obaidi, Mustafa ; Pereboeva, Larisa ; Salzman, Donna ; Erba, Harry P ; Lamb, Lawrence S ; Bhatia, Ravi ; Mineishi, Shin ; Di Stasi, Antonio</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c725t-3388fafec0e32cd5bfa39e5bff958423c4bd0e714c218e4be858f3155d33e2b93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Acute myelocytic leukemia</topic><topic>Acute myeloid leukemia</topic><topic>Antigens</topic><topic>Antitumor activity</topic><topic>Apoptosis</topic><topic>B7-H1 Antigen - pharmacology</topic><topic>Bcl-2 protein</topic><topic>Biology and Life Sciences</topic><topic>Biphenyl Compounds - pharmacology</topic><topic>Bridged Bicyclo Compounds, Heterocyclic - pharmacology</topic><topic>Cancer</topic><topic>Care and treatment</topic><topic>Caspase 9 - genetics</topic><topic>Caspase 9 - immunology</topic><topic>Cell Engineering</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Cellular Reprogramming</topic><topic>Chemotherapy</topic><topic>Chimeric antigen receptors</topic><topic>Clinical Trials as Topic</topic><topic>Cyclophosphamide - analogs & derivatives</topic><topic>Cyclophosphamide - pharmacology</topic><topic>Cytokines</topic><topic>Cytotoxicity, Immunologic</topic><topic>Degranulation</topic><topic>Drug dosages</topic><topic>Gene therapy</topic><topic>Genetic modification</topic><topic>Genetic Vectors</topic><topic>Granulocytes</topic><topic>Hematology</topic><topic>Hematopoietic stem cells</topic><topic>Humans</topic><topic>Immunology</topic><topic>Immunotherapy</topic><topic>Inhibitors</topic><topic>Interferon</topic><topic>Interferon-gamma - biosynthesis</topic><topic>Interferon-gamma - immunology</topic><topic>Leukemia</topic><topic>Leukemia, Myeloid, Acute - genetics</topic><topic>Leukemia, Myeloid, Acute - immunology</topic><topic>Leukemia, Myeloid, Acute - pathology</topic><topic>Leukemia, Myeloid, Acute - therapy</topic><topic>Ligands</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Lysosomal-Associated Membrane Protein 1 - genetics</topic><topic>Lysosomal-Associated Membrane Protein 1 - immunology</topic><topic>Medicine and Health Sciences</topic><topic>Mental health</topic><topic>Myeloid Cells - drug effects</topic><topic>Myeloid Cells - immunology</topic><topic>Myeloid Cells - pathology</topic><topic>Myeloid leukemia</topic><topic>Nitrophenols - pharmacology</topic><topic>Oncology</topic><topic>Patients</topic><topic>Piperazines - pharmacology</topic><topic>Primary Cell Culture</topic><topic>Receptors, Antigen, T-Cell - genetics</topic><topic>Receptors, Antigen, T-Cell - immunology</topic><topic>Recombinant Fusion Proteins - genetics</topic><topic>Recombinant Fusion Proteins - immunology</topic><topic>Research and Analysis Methods</topic><topic>Risk groups</topic><topic>Safety measures</topic><topic>Sialic Acid Binding Ig-like Lectin 3 - antagonists & inhibitors</topic><topic>Sialic Acid Binding Ig-like Lectin 3 - genetics</topic><topic>Sialic Acid Binding Ig-like Lectin 3 - immunology</topic><topic>Standard error</topic><topic>Stem cell transplantation</topic><topic>Stem cells</topic><topic>Studies</topic><topic>Suicidal behavior</topic><topic>Suicide</topic><topic>Suicide genes</topic><topic>Sulfonamides - pharmacology</topic><topic>T cell receptors</topic><topic>T cells</topic><topic>T-Lymphocytes - cytology</topic><topic>T-Lymphocytes - drug effects</topic><topic>T-Lymphocytes - immunology</topic><topic>Transplants & implants</topic><topic>Tumor Necrosis Factor-alpha - biosynthesis</topic><topic>Tumor Necrosis Factor-alpha - immunology</topic><topic>Tumor necrosis factor-α</topic><topic>γ-Interferon</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Minagawa, Kentaro</creatorcontrib><creatorcontrib>Jamil, Muhammad O</creatorcontrib><creatorcontrib>Al-Obaidi, Mustafa</creatorcontrib><creatorcontrib>Pereboeva, Larisa</creatorcontrib><creatorcontrib>Salzman, Donna</creatorcontrib><creatorcontrib>Erba, Harry P</creatorcontrib><creatorcontrib>Lamb, Lawrence S</creatorcontrib><creatorcontrib>Bhatia, Ravi</creatorcontrib><creatorcontrib>Mineishi, Shin</creatorcontrib><creatorcontrib>Di Stasi, Antonio</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Minagawa, Kentaro</au><au>Jamil, Muhammad O</au><au>Al-Obaidi, Mustafa</au><au>Pereboeva, Larisa</au><au>Salzman, Donna</au><au>Erba, Harry P</au><au>Lamb, Lawrence S</au><au>Bhatia, Ravi</au><au>Mineishi, Shin</au><au>Di Stasi, Antonio</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>In Vitro Pre-Clinical Validation of Suicide Gene Modified Anti-CD33 Redirected Chimeric Antigen Receptor T-Cells for Acute Myeloid Leukemia</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2016-12-01</date><risdate>2016</risdate><volume>11</volume><issue>12</issue><spage>e0166891</spage><pages>e0166891-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Approximately fifty percent of patients with acute myeloid leukemia can be cured with current therapeutic strategies which include, standard dose chemotherapy for patients at standard risk of relapse as assessed by cytogenetic and molecular analysis, or high-dose chemotherapy with allogeneic hematopoietic stem cell transplant for high-risk patients. Despite allogeneic hematopoietic stem cell transplant about 25% of patients still succumb to disease relapse, therefore, novel strategies are needed to improve the outcome of patients with acute myeloid leukemia.
We developed an immunotherapeutic strategy targeting the CD33 myeloid antigen, expressed in ~ 85-90% of patients with acute myeloid leukemia, using chimeric antigen receptor redirected T-cells. Considering that administration of CAR T-cells has been associated with cytokine release syndrome and other potential off-tumor effects in patients, safety measures were here investigated and reported. We genetically modified human activated T-cells from healthy donors or patients with acute myeloid leukemia with retroviral supernatant encoding the inducible Caspase9 suicide gene, a ΔCD19 selectable marker, and a humanized third generation chimeric antigen receptor recognizing human CD33. ΔCD19 selected inducible Caspase9-CAR.CD33 T-cells had a 75±3.8% (average ± standard error of the mean) chimeric antigen receptor expression, were able to specifically lyse CD33+ targets in vitro, including freshly isolated leukemic blasts from patients, produce significant amount of tumor-necrosis-factor-alpha and interferon-gamma, express the CD107a degranulation marker, and proliferate upon antigen specific stimulation. Challenging ΔCD19 selected inducible Caspase9-CAR.CD33 T-cells with programmed-death-ligand-1 enriched leukemia blasts resulted in significant killing like observed for the programmed-death-ligand-1 negative leukemic blasts fraction. Since the administration of 10 nanomolar of a non-therapeutic dimerizer to activate the suicide gene resulted in the elimination of only 76.4±2.0% gene modified cells in vitro, we found that co-administration of the dimerizer with either the BCL-2 inhibitor ABT-199, the pan-BCL inhibitor ABT-737, or mafosfamide, resulted in an additive effect up to complete cell elimination.
This strategy could be investigated for the safety of CAR T-cell applications, and targeting CD33 could be used as a 'bridge" therapy for patients coming to allogeneic hematopoietic stem cell transplant, as anti-leukemia activity from infusing CAR.CD33 T-cells has been demonstrated in an ongoing clinical trial. Albeit never performed in the clinical setting, our future plan is to investigate the utility of iC9-CAR.CD33 T-cells as part of the conditioning therapy for an allogeneic hematopoietic stem cell transplant for acute myeloid leukemia, together with other myelosuppressive agents, whilst the activation of the inducible Caspase9 suicide gene would grant elimination of the infused gene modified T-cells prior to stem cell infusion to reduce the risk of engraftment failure as the CD33 is also expressed on a proportion of the donor stem cell graft.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>27907031</pmid><doi>10.1371/journal.pone.0166891</doi><tpages>e0166891</tpages><orcidid>https://orcid.org/0000-0002-7886-3514</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2016-12, Vol.11 (12), p.e0166891 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1845246541 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Acute myelocytic leukemia Acute myeloid leukemia Antigens Antitumor activity Apoptosis B7-H1 Antigen - pharmacology Bcl-2 protein Biology and Life Sciences Biphenyl Compounds - pharmacology Bridged Bicyclo Compounds, Heterocyclic - pharmacology Cancer Care and treatment Caspase 9 - genetics Caspase 9 - immunology Cell Engineering Cell Line, Tumor Cell Proliferation - drug effects Cellular Reprogramming Chemotherapy Chimeric antigen receptors Clinical Trials as Topic Cyclophosphamide - analogs & derivatives Cyclophosphamide - pharmacology Cytokines Cytotoxicity, Immunologic Degranulation Drug dosages Gene therapy Genetic modification Genetic Vectors Granulocytes Hematology Hematopoietic stem cells Humans Immunology Immunotherapy Inhibitors Interferon Interferon-gamma - biosynthesis Interferon-gamma - immunology Leukemia Leukemia, Myeloid, Acute - genetics Leukemia, Myeloid, Acute - immunology Leukemia, Myeloid, Acute - pathology Leukemia, Myeloid, Acute - therapy Ligands Lymphocytes Lymphocytes T Lysosomal-Associated Membrane Protein 1 - genetics Lysosomal-Associated Membrane Protein 1 - immunology Medicine and Health Sciences Mental health Myeloid Cells - drug effects Myeloid Cells - immunology Myeloid Cells - pathology Myeloid leukemia Nitrophenols - pharmacology Oncology Patients Piperazines - pharmacology Primary Cell Culture Receptors, Antigen, T-Cell - genetics Receptors, Antigen, T-Cell - immunology Recombinant Fusion Proteins - genetics Recombinant Fusion Proteins - immunology Research and Analysis Methods Risk groups Safety measures Sialic Acid Binding Ig-like Lectin 3 - antagonists & inhibitors Sialic Acid Binding Ig-like Lectin 3 - genetics Sialic Acid Binding Ig-like Lectin 3 - immunology Standard error Stem cell transplantation Stem cells Studies Suicidal behavior Suicide Suicide genes Sulfonamides - pharmacology T cell receptors T cells T-Lymphocytes - cytology T-Lymphocytes - drug effects T-Lymphocytes - immunology Transplants & implants Tumor Necrosis Factor-alpha - biosynthesis Tumor Necrosis Factor-alpha - immunology Tumor necrosis factor-α γ-Interferon |
| title | In Vitro Pre-Clinical Validation of Suicide Gene Modified Anti-CD33 Redirected Chimeric Antigen Receptor T-Cells for Acute Myeloid Leukemia |
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