Constitutively active MyD88/CD40 costimulation enhances expansion and efficacy of chimeric antigen receptor T cells targeting hematological malignancies
Successful adoptive chimeric antigen receptor (CAR) T-cell therapies against hematological malignancies require CAR-T expansion and durable persistence following infusion. Balancing increased CAR-T potency with safety, including severe cytokine-release syndrome (sCRS) and neurotoxicity, warrants inc...
Gespeichert in:
| Veröffentlicht in: | Leukemia 2019-09, Vol.33 (9), p.2195-2207 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 2207 |
|---|---|
| container_issue | 9 |
| container_start_page | 2195 |
| container_title | Leukemia |
| container_volume | 33 |
| creator | Collinson-Pautz, Matthew R. Chang, Wei-Chun Lu, An Khalil, Mariam Crisostomo, Jeannette W. Lin, Pei-Yi Mahendravada, Aruna Shinners, Nicholas P. Brandt, Mary E. Zhang, Ming Duong, MyLinh Bayle, J. Henri Slawin, Kevin M. Spencer, David M. Foster, Aaron E. |
| description | Successful adoptive chimeric antigen receptor (CAR) T-cell therapies against hematological malignancies require CAR-T expansion and durable persistence following infusion. Balancing increased CAR-T potency with safety, including severe cytokine-release syndrome (sCRS) and neurotoxicity, warrants inclusion of safety mechanisms to control in vivo CAR-T activity. Here, we describe a novel CAR-T cell platform that utilizes expression of the toll-like receptor (TLR) adaptor molecule, MyD88, and tumor-necrosis factor family member, CD40 (MC), tethered to the CAR molecule through an intentionally inefficient 2A linker system, providing a constitutive signal that drives CAR-T survival, proliferation, and antitumor activity against CD19
+
and CD123
+
hematological cancers. Robust activity of MC-enhanced CAR-T cells was associated with cachexia in animal models that corresponded with high levels of human cytokine production. However, toxicity could be successfully resolved by using the inducible caspase-9 (iC9) safety switch to reduce serum cytokines, by administration of a neutralizing antibody against TNF-α, or by selecting “low” cytokine-producing CD8
+
T cells, without loss of antitumor activity. Interestingly, high basal activity was essential for in vivo CAR-T expansion. This study shows that co-opting novel signaling elements (i.e., MyD88 and CD40) and development of a unique CAR-T architecture can drive T-cell proliferation in vivo to enhance CAR-T therapies. |
| doi_str_mv | 10.1038/s41375-019-0417-9 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6756044</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A598451096</galeid><sourcerecordid>A598451096</sourcerecordid><originalsourceid>FETCH-LOGICAL-c568t-8098f40b6f312af41e90f28611dfa5e9f5b92357afeda34af3ee744bbdfb8ea13</originalsourceid><addsrcrecordid>eNp1kstu3CAYha2qVTNN-wDdVEiVunMCNth4Uyma9Cal6iZdI4x_bCIMU8BR5k36uMWaNMlIrViAON854nKK4i3BZwTX_DxSUresxKQrMSVt2T0rNoS2TckYI8-LDea8LZuuoifFqxhvMF7F5mVxUmNOmrpqN8XvrXcxmbQkcwt2j6RaF-j7_pLz8-0lxUj5rM-Llcl4h8BN0imICO520sV1S7oBgdZGSbVHXiM1mRmCUVlIZgSHAijYJR_QNVJgbURJhhGScSOaYJbJWz9mt0WztGZ0Od9AfF280NJGeHM_nxY_P3-63n4tr358-ba9uCoVa3gqOe64prhvdE0qqSmBDuuKN4QMWjLoNOu7qmat1DDImkpdA7SU9v2gew6S1KfFx0PubulnGBS4FKQVu2BmGfbCSyOOFWcmMfpb0bSswZTmgPf3AcH_WiAmceOX4PKZRVVxyvIJWfNIjdKCME77HKZmE5W4YF3GCO5W6uwfVB4DzEZ5B9rk_SPDhyeGCaRNU_R2Wf8qHoPkAKrgYwygH25IsFjLJA5lErlMYi2T6LLn3dOneXD8bU8GqgMQs-RGCI9X_3_qHyx617E</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2284580956</pqid></control><display><type>article</type><title>Constitutively active MyD88/CD40 costimulation enhances expansion and efficacy of chimeric antigen receptor T cells targeting hematological malignancies</title><source>MEDLINE</source><source>SpringerLink Journals - AutoHoldings</source><creator>Collinson-Pautz, Matthew R. ; Chang, Wei-Chun ; Lu, An ; Khalil, Mariam ; Crisostomo, Jeannette W. ; Lin, Pei-Yi ; Mahendravada, Aruna ; Shinners, Nicholas P. ; Brandt, Mary E. ; Zhang, Ming ; Duong, MyLinh ; Bayle, J. Henri ; Slawin, Kevin M. ; Spencer, David M. ; Foster, Aaron E.</creator><creatorcontrib>Collinson-Pautz, Matthew R. ; Chang, Wei-Chun ; Lu, An ; Khalil, Mariam ; Crisostomo, Jeannette W. ; Lin, Pei-Yi ; Mahendravada, Aruna ; Shinners, Nicholas P. ; Brandt, Mary E. ; Zhang, Ming ; Duong, MyLinh ; Bayle, J. Henri ; Slawin, Kevin M. ; Spencer, David M. ; Foster, Aaron E.</creatorcontrib><description>Successful adoptive chimeric antigen receptor (CAR) T-cell therapies against hematological malignancies require CAR-T expansion and durable persistence following infusion. Balancing increased CAR-T potency with safety, including severe cytokine-release syndrome (sCRS) and neurotoxicity, warrants inclusion of safety mechanisms to control in vivo CAR-T activity. Here, we describe a novel CAR-T cell platform that utilizes expression of the toll-like receptor (TLR) adaptor molecule, MyD88, and tumor-necrosis factor family member, CD40 (MC), tethered to the CAR molecule through an intentionally inefficient 2A linker system, providing a constitutive signal that drives CAR-T survival, proliferation, and antitumor activity against CD19
+
and CD123
+
hematological cancers. Robust activity of MC-enhanced CAR-T cells was associated with cachexia in animal models that corresponded with high levels of human cytokine production. However, toxicity could be successfully resolved by using the inducible caspase-9 (iC9) safety switch to reduce serum cytokines, by administration of a neutralizing antibody against TNF-α, or by selecting “low” cytokine-producing CD8
+
T cells, without loss of antitumor activity. Interestingly, high basal activity was essential for in vivo CAR-T expansion. This study shows that co-opting novel signaling elements (i.e., MyD88 and CD40) and development of a unique CAR-T architecture can drive T-cell proliferation in vivo to enhance CAR-T therapies.</description><identifier>ISSN: 0887-6924</identifier><identifier>EISSN: 1476-5551</identifier><identifier>DOI: 10.1038/s41375-019-0417-9</identifier><identifier>PMID: 30816327</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/2 ; 13/31 ; 14/5 ; 42/44 ; 631/250/251 ; 631/67/1059/2325 ; 64/60 ; 82 ; 82/29 ; 96/106 ; Animal models ; Animals ; Antibodies ; Anticancer properties ; Antigens ; Antigens, CD19 - immunology ; Antitumor activity ; Biocompatibility ; Blood cancer ; Blood diseases ; Cachexia ; Cancer Research ; Care and treatment ; Caspase ; Caspase-9 ; CD123 antigen ; CD19 antigen ; CD40 antigen ; CD40 Antigens - immunology ; CD8 antigen ; CD8-Positive T-Lymphocytes - immunology ; Cell proliferation ; Cell Proliferation - drug effects ; Chimeric antigen receptors ; Critical Care Medicine ; Cytokines ; Expansion ; Genetic aspects ; HEK293 Cells ; Hematologic Neoplasms - immunology ; Hematologic Neoplasms - therapy ; Hematology ; Humans ; Immune system ; Immunity ; Immunotherapy, Adoptive - methods ; In vivo methods and tests ; Intensive ; Internal Medicine ; Lymphocyte Activation - immunology ; Lymphocytes ; Lymphocytes T ; Medicine ; Medicine & Public Health ; Mice ; Mice, Inbred NOD ; MyD88 protein ; Myeloid Differentiation Factor 88 - immunology ; Neurotoxicity ; Oncology ; Proteins ; Receptors, Antigen, T-Cell - immunology ; Receptors, Chimeric Antigen - immunology ; Safety ; Signal Transduction - immunology ; T cells ; THP-1 Cells ; Toll-like receptors ; Toxicity ; Tumor necrosis factor-α</subject><ispartof>Leukemia, 2019-09, Vol.33 (9), p.2195-2207</ispartof><rights>The Author(s) 2019</rights><rights>COPYRIGHT 2019 Nature Publishing Group</rights><rights>This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c568t-8098f40b6f312af41e90f28611dfa5e9f5b92357afeda34af3ee744bbdfb8ea13</citedby><cites>FETCH-LOGICAL-c568t-8098f40b6f312af41e90f28611dfa5e9f5b92357afeda34af3ee744bbdfb8ea13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41375-019-0417-9$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41375-019-0417-9$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30816327$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Collinson-Pautz, Matthew R.</creatorcontrib><creatorcontrib>Chang, Wei-Chun</creatorcontrib><creatorcontrib>Lu, An</creatorcontrib><creatorcontrib>Khalil, Mariam</creatorcontrib><creatorcontrib>Crisostomo, Jeannette W.</creatorcontrib><creatorcontrib>Lin, Pei-Yi</creatorcontrib><creatorcontrib>Mahendravada, Aruna</creatorcontrib><creatorcontrib>Shinners, Nicholas P.</creatorcontrib><creatorcontrib>Brandt, Mary E.</creatorcontrib><creatorcontrib>Zhang, Ming</creatorcontrib><creatorcontrib>Duong, MyLinh</creatorcontrib><creatorcontrib>Bayle, J. Henri</creatorcontrib><creatorcontrib>Slawin, Kevin M.</creatorcontrib><creatorcontrib>Spencer, David M.</creatorcontrib><creatorcontrib>Foster, Aaron E.</creatorcontrib><title>Constitutively active MyD88/CD40 costimulation enhances expansion and efficacy of chimeric antigen receptor T cells targeting hematological malignancies</title><title>Leukemia</title><addtitle>Leukemia</addtitle><addtitle>Leukemia</addtitle><description>Successful adoptive chimeric antigen receptor (CAR) T-cell therapies against hematological malignancies require CAR-T expansion and durable persistence following infusion. Balancing increased CAR-T potency with safety, including severe cytokine-release syndrome (sCRS) and neurotoxicity, warrants inclusion of safety mechanisms to control in vivo CAR-T activity. Here, we describe a novel CAR-T cell platform that utilizes expression of the toll-like receptor (TLR) adaptor molecule, MyD88, and tumor-necrosis factor family member, CD40 (MC), tethered to the CAR molecule through an intentionally inefficient 2A linker system, providing a constitutive signal that drives CAR-T survival, proliferation, and antitumor activity against CD19
+
and CD123
+
hematological cancers. Robust activity of MC-enhanced CAR-T cells was associated with cachexia in animal models that corresponded with high levels of human cytokine production. However, toxicity could be successfully resolved by using the inducible caspase-9 (iC9) safety switch to reduce serum cytokines, by administration of a neutralizing antibody against TNF-α, or by selecting “low” cytokine-producing CD8
+
T cells, without loss of antitumor activity. Interestingly, high basal activity was essential for in vivo CAR-T expansion. This study shows that co-opting novel signaling elements (i.e., MyD88 and CD40) and development of a unique CAR-T architecture can drive T-cell proliferation in vivo to enhance CAR-T therapies.</description><subject>13/2</subject><subject>13/31</subject><subject>14/5</subject><subject>42/44</subject><subject>631/250/251</subject><subject>631/67/1059/2325</subject><subject>64/60</subject><subject>82</subject><subject>82/29</subject><subject>96/106</subject><subject>Animal models</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Anticancer properties</subject><subject>Antigens</subject><subject>Antigens, CD19 - immunology</subject><subject>Antitumor activity</subject><subject>Biocompatibility</subject><subject>Blood cancer</subject><subject>Blood diseases</subject><subject>Cachexia</subject><subject>Cancer Research</subject><subject>Care and treatment</subject><subject>Caspase</subject><subject>Caspase-9</subject><subject>CD123 antigen</subject><subject>CD19 antigen</subject><subject>CD40 antigen</subject><subject>CD40 Antigens - immunology</subject><subject>CD8 antigen</subject><subject>CD8-Positive T-Lymphocytes - immunology</subject><subject>Cell proliferation</subject><subject>Cell Proliferation - drug effects</subject><subject>Chimeric antigen receptors</subject><subject>Critical Care Medicine</subject><subject>Cytokines</subject><subject>Expansion</subject><subject>Genetic aspects</subject><subject>HEK293 Cells</subject><subject>Hematologic Neoplasms - immunology</subject><subject>Hematologic Neoplasms - therapy</subject><subject>Hematology</subject><subject>Humans</subject><subject>Immune system</subject><subject>Immunity</subject><subject>Immunotherapy, Adoptive - methods</subject><subject>In vivo methods and tests</subject><subject>Intensive</subject><subject>Internal Medicine</subject><subject>Lymphocyte Activation - immunology</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice</subject><subject>Mice, Inbred NOD</subject><subject>MyD88 protein</subject><subject>Myeloid Differentiation Factor 88 - immunology</subject><subject>Neurotoxicity</subject><subject>Oncology</subject><subject>Proteins</subject><subject>Receptors, Antigen, T-Cell - immunology</subject><subject>Receptors, Chimeric Antigen - immunology</subject><subject>Safety</subject><subject>Signal Transduction - immunology</subject><subject>T cells</subject><subject>THP-1 Cells</subject><subject>Toll-like receptors</subject><subject>Toxicity</subject><subject>Tumor necrosis factor-α</subject><issn>0887-6924</issn><issn>1476-5551</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kstu3CAYha2qVTNN-wDdVEiVunMCNth4Uyma9Cal6iZdI4x_bCIMU8BR5k36uMWaNMlIrViAON854nKK4i3BZwTX_DxSUresxKQrMSVt2T0rNoS2TckYI8-LDea8LZuuoifFqxhvMF7F5mVxUmNOmrpqN8XvrXcxmbQkcwt2j6RaF-j7_pLz8-0lxUj5rM-Llcl4h8BN0imICO520sV1S7oBgdZGSbVHXiM1mRmCUVlIZgSHAijYJR_QNVJgbURJhhGScSOaYJbJWz9mt0WztGZ0Od9AfF280NJGeHM_nxY_P3-63n4tr358-ba9uCoVa3gqOe64prhvdE0qqSmBDuuKN4QMWjLoNOu7qmat1DDImkpdA7SU9v2gew6S1KfFx0PubulnGBS4FKQVu2BmGfbCSyOOFWcmMfpb0bSswZTmgPf3AcH_WiAmceOX4PKZRVVxyvIJWfNIjdKCME77HKZmE5W4YF3GCO5W6uwfVB4DzEZ5B9rk_SPDhyeGCaRNU_R2Wf8qHoPkAKrgYwygH25IsFjLJA5lErlMYi2T6LLn3dOneXD8bU8GqgMQs-RGCI9X_3_qHyx617E</recordid><startdate>20190901</startdate><enddate>20190901</enddate><creator>Collinson-Pautz, Matthew R.</creator><creator>Chang, Wei-Chun</creator><creator>Lu, An</creator><creator>Khalil, Mariam</creator><creator>Crisostomo, Jeannette W.</creator><creator>Lin, Pei-Yi</creator><creator>Mahendravada, Aruna</creator><creator>Shinners, Nicholas P.</creator><creator>Brandt, Mary E.</creator><creator>Zhang, Ming</creator><creator>Duong, MyLinh</creator><creator>Bayle, J. Henri</creator><creator>Slawin, Kevin M.</creator><creator>Spencer, David M.</creator><creator>Foster, Aaron E.</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><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>3V.</scope><scope>7QL</scope><scope>7RV</scope><scope>7T5</scope><scope>7T7</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</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>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>5PM</scope></search><sort><creationdate>20190901</creationdate><title>Constitutively active MyD88/CD40 costimulation enhances expansion and efficacy of chimeric antigen receptor T cells targeting hematological malignancies</title><author>Collinson-Pautz, Matthew R. ; Chang, Wei-Chun ; Lu, An ; Khalil, Mariam ; Crisostomo, Jeannette W. ; Lin, Pei-Yi ; Mahendravada, Aruna ; Shinners, Nicholas P. ; Brandt, Mary E. ; Zhang, Ming ; Duong, MyLinh ; Bayle, J. Henri ; Slawin, Kevin M. ; Spencer, David M. ; Foster, Aaron E.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c568t-8098f40b6f312af41e90f28611dfa5e9f5b92357afeda34af3ee744bbdfb8ea13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>13/2</topic><topic>13/31</topic><topic>14/5</topic><topic>42/44</topic><topic>631/250/251</topic><topic>631/67/1059/2325</topic><topic>64/60</topic><topic>82</topic><topic>82/29</topic><topic>96/106</topic><topic>Animal models</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Anticancer properties</topic><topic>Antigens</topic><topic>Antigens, CD19 - immunology</topic><topic>Antitumor activity</topic><topic>Biocompatibility</topic><topic>Blood cancer</topic><topic>Blood diseases</topic><topic>Cachexia</topic><topic>Cancer Research</topic><topic>Care and treatment</topic><topic>Caspase</topic><topic>Caspase-9</topic><topic>CD123 antigen</topic><topic>CD19 antigen</topic><topic>CD40 antigen</topic><topic>CD40 Antigens - immunology</topic><topic>CD8 antigen</topic><topic>CD8-Positive T-Lymphocytes - immunology</topic><topic>Cell proliferation</topic><topic>Cell Proliferation - drug effects</topic><topic>Chimeric antigen receptors</topic><topic>Critical Care Medicine</topic><topic>Cytokines</topic><topic>Expansion</topic><topic>Genetic aspects</topic><topic>HEK293 Cells</topic><topic>Hematologic Neoplasms - immunology</topic><topic>Hematologic Neoplasms - therapy</topic><topic>Hematology</topic><topic>Humans</topic><topic>Immune system</topic><topic>Immunity</topic><topic>Immunotherapy, Adoptive - methods</topic><topic>In vivo methods and tests</topic><topic>Intensive</topic><topic>Internal Medicine</topic><topic>Lymphocyte Activation - immunology</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mice</topic><topic>Mice, Inbred NOD</topic><topic>MyD88 protein</topic><topic>Myeloid Differentiation Factor 88 - immunology</topic><topic>Neurotoxicity</topic><topic>Oncology</topic><topic>Proteins</topic><topic>Receptors, Antigen, T-Cell - immunology</topic><topic>Receptors, Chimeric Antigen - immunology</topic><topic>Safety</topic><topic>Signal Transduction - immunology</topic><topic>T cells</topic><topic>THP-1 Cells</topic><topic>Toll-like receptors</topic><topic>Toxicity</topic><topic>Tumor necrosis factor-α</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Collinson-Pautz, Matthew R.</creatorcontrib><creatorcontrib>Chang, Wei-Chun</creatorcontrib><creatorcontrib>Lu, An</creatorcontrib><creatorcontrib>Khalil, Mariam</creatorcontrib><creatorcontrib>Crisostomo, Jeannette W.</creatorcontrib><creatorcontrib>Lin, Pei-Yi</creatorcontrib><creatorcontrib>Mahendravada, Aruna</creatorcontrib><creatorcontrib>Shinners, Nicholas P.</creatorcontrib><creatorcontrib>Brandt, Mary E.</creatorcontrib><creatorcontrib>Zhang, Ming</creatorcontrib><creatorcontrib>Duong, MyLinh</creatorcontrib><creatorcontrib>Bayle, J. Henri</creatorcontrib><creatorcontrib>Slawin, Kevin M.</creatorcontrib><creatorcontrib>Spencer, David M.</creatorcontrib><creatorcontrib>Foster, Aaron E.</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Nursing & Allied Health Database</collection><collection>Immunology Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</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 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>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</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>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</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>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</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>PubMed Central (Full Participant titles)</collection><jtitle>Leukemia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Collinson-Pautz, Matthew R.</au><au>Chang, Wei-Chun</au><au>Lu, An</au><au>Khalil, Mariam</au><au>Crisostomo, Jeannette W.</au><au>Lin, Pei-Yi</au><au>Mahendravada, Aruna</au><au>Shinners, Nicholas P.</au><au>Brandt, Mary E.</au><au>Zhang, Ming</au><au>Duong, MyLinh</au><au>Bayle, J. Henri</au><au>Slawin, Kevin M.</au><au>Spencer, David M.</au><au>Foster, Aaron E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Constitutively active MyD88/CD40 costimulation enhances expansion and efficacy of chimeric antigen receptor T cells targeting hematological malignancies</atitle><jtitle>Leukemia</jtitle><stitle>Leukemia</stitle><addtitle>Leukemia</addtitle><date>2019-09-01</date><risdate>2019</risdate><volume>33</volume><issue>9</issue><spage>2195</spage><epage>2207</epage><pages>2195-2207</pages><issn>0887-6924</issn><eissn>1476-5551</eissn><abstract>Successful adoptive chimeric antigen receptor (CAR) T-cell therapies against hematological malignancies require CAR-T expansion and durable persistence following infusion. Balancing increased CAR-T potency with safety, including severe cytokine-release syndrome (sCRS) and neurotoxicity, warrants inclusion of safety mechanisms to control in vivo CAR-T activity. Here, we describe a novel CAR-T cell platform that utilizes expression of the toll-like receptor (TLR) adaptor molecule, MyD88, and tumor-necrosis factor family member, CD40 (MC), tethered to the CAR molecule through an intentionally inefficient 2A linker system, providing a constitutive signal that drives CAR-T survival, proliferation, and antitumor activity against CD19
+
and CD123
+
hematological cancers. Robust activity of MC-enhanced CAR-T cells was associated with cachexia in animal models that corresponded with high levels of human cytokine production. However, toxicity could be successfully resolved by using the inducible caspase-9 (iC9) safety switch to reduce serum cytokines, by administration of a neutralizing antibody against TNF-α, or by selecting “low” cytokine-producing CD8
+
T cells, without loss of antitumor activity. Interestingly, high basal activity was essential for in vivo CAR-T expansion. This study shows that co-opting novel signaling elements (i.e., MyD88 and CD40) and development of a unique CAR-T architecture can drive T-cell proliferation in vivo to enhance CAR-T therapies.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>30816327</pmid><doi>10.1038/s41375-019-0417-9</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0887-6924 |
| ispartof | Leukemia, 2019-09, Vol.33 (9), p.2195-2207 |
| issn | 0887-6924 1476-5551 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6756044 |
| source | MEDLINE; SpringerLink Journals - AutoHoldings |
| subjects | 13/2 13/31 14/5 42/44 631/250/251 631/67/1059/2325 64/60 82 82/29 96/106 Animal models Animals Antibodies Anticancer properties Antigens Antigens, CD19 - immunology Antitumor activity Biocompatibility Blood cancer Blood diseases Cachexia Cancer Research Care and treatment Caspase Caspase-9 CD123 antigen CD19 antigen CD40 antigen CD40 Antigens - immunology CD8 antigen CD8-Positive T-Lymphocytes - immunology Cell proliferation Cell Proliferation - drug effects Chimeric antigen receptors Critical Care Medicine Cytokines Expansion Genetic aspects HEK293 Cells Hematologic Neoplasms - immunology Hematologic Neoplasms - therapy Hematology Humans Immune system Immunity Immunotherapy, Adoptive - methods In vivo methods and tests Intensive Internal Medicine Lymphocyte Activation - immunology Lymphocytes Lymphocytes T Medicine Medicine & Public Health Mice Mice, Inbred NOD MyD88 protein Myeloid Differentiation Factor 88 - immunology Neurotoxicity Oncology Proteins Receptors, Antigen, T-Cell - immunology Receptors, Chimeric Antigen - immunology Safety Signal Transduction - immunology T cells THP-1 Cells Toll-like receptors Toxicity Tumor necrosis factor-α |
| title | Constitutively active MyD88/CD40 costimulation enhances expansion and efficacy of chimeric antigen receptor T cells targeting hematological malignancies |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-09T03%3A44%3A44IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Constitutively%20active%20MyD88/CD40%20costimulation%20enhances%20expansion%20and%20efficacy%20of%20chimeric%20antigen%20receptor%20T%20cells%20targeting%20hematological%20malignancies&rft.jtitle=Leukemia&rft.au=Collinson-Pautz,%20Matthew%20R.&rft.date=2019-09-01&rft.volume=33&rft.issue=9&rft.spage=2195&rft.epage=2207&rft.pages=2195-2207&rft.issn=0887-6924&rft.eissn=1476-5551&rft_id=info:doi/10.1038/s41375-019-0417-9&rft_dat=%3Cgale_pubme%3EA598451096%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2284580956&rft_id=info:pmid/30816327&rft_galeid=A598451096&rfr_iscdi=true |