Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial
Chimeric antigen receptor (CAR) T cells targeting CD19 are a breakthrough treatment for relapsed, refractory B cell malignancies 1 – 5 . Despite impressive outcomes, relapse with CD19 − disease remains a challenge. We address this limitation through a first-in-human trial of bispecific anti-CD20, an...
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| Veröffentlicht in: | Nature medicine 2020-10, Vol.26 (10), p.1569-1575 |
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| creator | Shah, Nirav N. Johnson, Bryon D. Schneider, Dina Zhu, Fenlu Szabo, Aniko Keever-Taylor, Carolyn A. Krueger, Winfried Worden, Andrew A. Kadan, Michael J. Yim, Sharon Cunningham, Ashley Hamadani, Mehdi Fenske, Timothy S. Dropulić, Boro Orentas, Rimas Hari, Parameswaran |
| description | Chimeric antigen receptor (CAR) T cells targeting CD19 are a breakthrough treatment for relapsed, refractory B cell malignancies
1
–
5
. Despite impressive outcomes, relapse with CD19
−
disease remains a challenge. We address this limitation through a first-in-human trial of bispecific anti-CD20, anti-CD19 (LV20.19) CAR T cells for relapsed, refractory B cell malignancies. Adult patients with B cell non-Hodgkin lymphoma or chronic lymphocytic leukemia were treated on a phase 1 dose escalation and expansion trial (
NCT03019055
) to evaluate the safety of 4-1BB–CD3ζ LV20.19 CAR T cells and the feasibility of on-site manufacturing using the CliniMACS Prodigy system. CAR T cell doses ranged from 2.5 × 10
5
–2.5 × 10
6
cells per kg. Cell manufacturing was set at 14 d with the goal of infusing non-cryopreserved LV20.19 CAR T cells. The target dose of LV20.19 CAR T cells was met in all CAR-naive patients, and 22 patients received LV20.19 CAR T cells on protocol. In the absence of dose-limiting toxicity, a dose of 2.5 × 10
6
cells per kg was chosen for expansion. Grade 3–4 cytokine release syndrome occurred in one (5%) patient, and grade 3–4 neurotoxicity occurred in three (14%) patients. Eighteen (82%) patients achieved an overall response at day 28, 14 (64%) had a complete response, and 4 (18%) had a partial response. The overall response rate to the dose of 2.5 × 10
6
cells per kg with non-cryopreserved infusion (
n
= 12) was 100% (complete response, 92%; partial response, 8%). Notably, loss of the CD19 antigen was not seen in patients who relapsed or experienced treatment failure. In conclusion, on-site manufacturing and infusion of non-cryopreserved LV20.19 CAR T cells were feasible and therapeutically safe, showing low toxicity and high efficacy. Bispecific CARs may improve clinical responses by mitigating target antigen downregulation as a mechanism of relapse.
A new bispecific CAR T cell product targeting the CD20 and CD19 antigens demonstrates an excellent safety profile and high clinical efficacy in patients with B cell non-Hodgkin lymphoma and chronic lymphocytic leukemia. |
| doi_str_mv | 10.1038/s41591-020-1081-3 |
| format | Article |
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1
–
5
. Despite impressive outcomes, relapse with CD19
−
disease remains a challenge. We address this limitation through a first-in-human trial of bispecific anti-CD20, anti-CD19 (LV20.19) CAR T cells for relapsed, refractory B cell malignancies. Adult patients with B cell non-Hodgkin lymphoma or chronic lymphocytic leukemia were treated on a phase 1 dose escalation and expansion trial (
NCT03019055
) to evaluate the safety of 4-1BB–CD3ζ LV20.19 CAR T cells and the feasibility of on-site manufacturing using the CliniMACS Prodigy system. CAR T cell doses ranged from 2.5 × 10
5
–2.5 × 10
6
cells per kg. Cell manufacturing was set at 14 d with the goal of infusing non-cryopreserved LV20.19 CAR T cells. The target dose of LV20.19 CAR T cells was met in all CAR-naive patients, and 22 patients received LV20.19 CAR T cells on protocol. In the absence of dose-limiting toxicity, a dose of 2.5 × 10
6
cells per kg was chosen for expansion. Grade 3–4 cytokine release syndrome occurred in one (5%) patient, and grade 3–4 neurotoxicity occurred in three (14%) patients. Eighteen (82%) patients achieved an overall response at day 28, 14 (64%) had a complete response, and 4 (18%) had a partial response. The overall response rate to the dose of 2.5 × 10
6
cells per kg with non-cryopreserved infusion (
n
= 12) was 100% (complete response, 92%; partial response, 8%). Notably, loss of the CD19 antigen was not seen in patients who relapsed or experienced treatment failure. In conclusion, on-site manufacturing and infusion of non-cryopreserved LV20.19 CAR T cells were feasible and therapeutically safe, showing low toxicity and high efficacy. Bispecific CARs may improve clinical responses by mitigating target antigen downregulation as a mechanism of relapse.
A new bispecific CAR T cell product targeting the CD20 and CD19 antigens demonstrates an excellent safety profile and high clinical efficacy in patients with B cell non-Hodgkin lymphoma and chronic lymphocytic leukemia.</description><identifier>ISSN: 1078-8956</identifier><identifier>EISSN: 1546-170X</identifier><identifier>DOI: 10.1038/s41591-020-1081-3</identifier><identifier>PMID: 33020647</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>631/250/251 ; 631/67/1990/283 ; 631/67/1990/291 ; Adult ; Aged ; Antigens ; Antigens, CD19 - immunology ; Antigens, CD20 - immunology ; B cells ; Biomedical and Life Sciences ; Biomedicine ; Cancer Research ; CD19 antigen ; CD20 antigen ; Chimeric antigen receptors ; Chronic lymphocytic leukemia ; Cryopreservation ; Diseases ; Dose-Response Relationship, Immunologic ; Down-regulation ; Effectiveness ; Feasibility ; Female ; Health aspects ; Health services ; Humans ; Immunotherapy ; Immunotherapy, Adoptive - methods ; Infectious Diseases ; Letter ; Leukemia ; Leukemia, B-Cell - immunology ; Leukemia, B-Cell - pathology ; Leukemia, B-Cell - therapy ; Lymphatic leukemia ; Lymphocyte Count ; Lymphocytes ; Lymphocytes T ; Lymphoma ; Lymphoma, B-Cell - immunology ; Lymphoma, B-Cell - pathology ; Lymphoma, B-Cell - therapy ; Male ; Malignancy ; Manufacturing ; Metabolic Diseases ; Methods ; Middle Aged ; Molecular Medicine ; Neurosciences ; Neurotoxicity ; Non-Hodgkin's lymphoma ; Onsite ; Patients ; Physiological aspects ; Receptors, Antigen, T-Cell - immunology ; Receptors, Chimeric Antigen - immunology ; Recurrence ; Relapse ; T cells ; T-Lymphocytes - cytology ; T-Lymphocytes - immunology ; T-Lymphocytes - metabolism ; T-Lymphocytes - transplantation ; Toxicity</subject><ispartof>Nature medicine, 2020-10, Vol.26 (10), p.1569-1575</ispartof><rights>The Author(s), under exclusive licence to Springer Nature America, Inc. 2020</rights><rights>COPYRIGHT 2020 Nature Publishing Group</rights><rights>The Author(s), under exclusive licence to Springer Nature America, Inc. 2020.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c624t-7d6e3d26786fb21ec5670029d4dbe79fb020b7567d4d74112f59717f8b6198a43</citedby><cites>FETCH-LOGICAL-c624t-7d6e3d26786fb21ec5670029d4dbe79fb020b7567d4d74112f59717f8b6198a43</cites><orcidid>0000-0002-8129-0614 ; 0000-0002-3861-7677 ; 0000-0002-3085-6876 ; 0000-0001-5372-510X ; 0000-0001-6442-1320 ; 0000-0002-4336-1071</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41591-020-1081-3$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41591-020-1081-3$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33020647$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shah, Nirav N.</creatorcontrib><creatorcontrib>Johnson, Bryon D.</creatorcontrib><creatorcontrib>Schneider, Dina</creatorcontrib><creatorcontrib>Zhu, Fenlu</creatorcontrib><creatorcontrib>Szabo, Aniko</creatorcontrib><creatorcontrib>Keever-Taylor, Carolyn A.</creatorcontrib><creatorcontrib>Krueger, Winfried</creatorcontrib><creatorcontrib>Worden, Andrew A.</creatorcontrib><creatorcontrib>Kadan, Michael J.</creatorcontrib><creatorcontrib>Yim, Sharon</creatorcontrib><creatorcontrib>Cunningham, Ashley</creatorcontrib><creatorcontrib>Hamadani, Mehdi</creatorcontrib><creatorcontrib>Fenske, Timothy S.</creatorcontrib><creatorcontrib>Dropulić, Boro</creatorcontrib><creatorcontrib>Orentas, Rimas</creatorcontrib><creatorcontrib>Hari, Parameswaran</creatorcontrib><title>Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial</title><title>Nature medicine</title><addtitle>Nat Med</addtitle><addtitle>Nat Med</addtitle><description>Chimeric antigen receptor (CAR) T cells targeting CD19 are a breakthrough treatment for relapsed, refractory B cell malignancies
1
–
5
. Despite impressive outcomes, relapse with CD19
−
disease remains a challenge. We address this limitation through a first-in-human trial of bispecific anti-CD20, anti-CD19 (LV20.19) CAR T cells for relapsed, refractory B cell malignancies. Adult patients with B cell non-Hodgkin lymphoma or chronic lymphocytic leukemia were treated on a phase 1 dose escalation and expansion trial (
NCT03019055
) to evaluate the safety of 4-1BB–CD3ζ LV20.19 CAR T cells and the feasibility of on-site manufacturing using the CliniMACS Prodigy system. CAR T cell doses ranged from 2.5 × 10
5
–2.5 × 10
6
cells per kg. Cell manufacturing was set at 14 d with the goal of infusing non-cryopreserved LV20.19 CAR T cells. The target dose of LV20.19 CAR T cells was met in all CAR-naive patients, and 22 patients received LV20.19 CAR T cells on protocol. In the absence of dose-limiting toxicity, a dose of 2.5 × 10
6
cells per kg was chosen for expansion. Grade 3–4 cytokine release syndrome occurred in one (5%) patient, and grade 3–4 neurotoxicity occurred in three (14%) patients. Eighteen (82%) patients achieved an overall response at day 28, 14 (64%) had a complete response, and 4 (18%) had a partial response. The overall response rate to the dose of 2.5 × 10
6
cells per kg with non-cryopreserved infusion (
n
= 12) was 100% (complete response, 92%; partial response, 8%). Notably, loss of the CD19 antigen was not seen in patients who relapsed or experienced treatment failure. In conclusion, on-site manufacturing and infusion of non-cryopreserved LV20.19 CAR T cells were feasible and therapeutically safe, showing low toxicity and high efficacy. Bispecific CARs may improve clinical responses by mitigating target antigen downregulation as a mechanism of relapse.
A new bispecific CAR T cell product targeting the CD20 and CD19 antigens demonstrates an excellent safety profile and high clinical efficacy in patients with B cell non-Hodgkin lymphoma and chronic lymphocytic leukemia.</description><subject>631/250/251</subject><subject>631/67/1990/283</subject><subject>631/67/1990/291</subject><subject>Adult</subject><subject>Aged</subject><subject>Antigens</subject><subject>Antigens, CD19 - immunology</subject><subject>Antigens, CD20 - immunology</subject><subject>B cells</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer Research</subject><subject>CD19 antigen</subject><subject>CD20 antigen</subject><subject>Chimeric antigen receptors</subject><subject>Chronic lymphocytic leukemia</subject><subject>Cryopreservation</subject><subject>Diseases</subject><subject>Dose-Response Relationship, Immunologic</subject><subject>Down-regulation</subject><subject>Effectiveness</subject><subject>Feasibility</subject><subject>Female</subject><subject>Health aspects</subject><subject>Health services</subject><subject>Humans</subject><subject>Immunotherapy</subject><subject>Immunotherapy, Adoptive - methods</subject><subject>Infectious Diseases</subject><subject>Letter</subject><subject>Leukemia</subject><subject>Leukemia, B-Cell - immunology</subject><subject>Leukemia, B-Cell - pathology</subject><subject>Leukemia, B-Cell - therapy</subject><subject>Lymphatic leukemia</subject><subject>Lymphocyte Count</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Lymphoma</subject><subject>Lymphoma, B-Cell - immunology</subject><subject>Lymphoma, B-Cell - pathology</subject><subject>Lymphoma, B-Cell - therapy</subject><subject>Male</subject><subject>Malignancy</subject><subject>Manufacturing</subject><subject>Metabolic Diseases</subject><subject>Methods</subject><subject>Middle Aged</subject><subject>Molecular Medicine</subject><subject>Neurosciences</subject><subject>Neurotoxicity</subject><subject>Non-Hodgkin's lymphoma</subject><subject>Onsite</subject><subject>Patients</subject><subject>Physiological aspects</subject><subject>Receptors, Antigen, T-Cell - immunology</subject><subject>Receptors, Chimeric Antigen - immunology</subject><subject>Recurrence</subject><subject>Relapse</subject><subject>T cells</subject><subject>T-Lymphocytes - cytology</subject><subject>T-Lymphocytes - immunology</subject><subject>T-Lymphocytes - metabolism</subject><subject>T-Lymphocytes - transplantation</subject><subject>Toxicity</subject><issn>1078-8956</issn><issn>1546-170X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqNkl1rFDEUhgdRbK3-AG8kIAiCqfmYSWZ6t12_CoVCreJdyGROZlOymTGZgYp_3qzbWhdWkFyckzfPe0JyTlE8p-SYEl6_TSWtGooJI5iSmmL-oDikVSkwleTbw5wTWeO6qcRB8SSla0IIJ1XzuDjgPHtEKQ-Ln6cujWCcdQbpMDm8fMfIm7uUNmi5uERXyID3Cdkhoghejwk6dPpbRGvtXR90MA7SCdJoXOkEiKJuyAGS0V5Pbgi5YofgZtQhbXZTdNo_LR5Z7RM8u41HxZcP76-Wn_D5xcez5eIcG8HKCctOAO-YkLWwLaNgKiEJYU1Xdi3Ixrb5La3MYhZkSSmzVSOptHUraFPrkh8VL7d1xzh8nyFN6nqYY8hXKlazmghRVvKe6rUH5YIdpqjN2iWjFoJLyaksWabwHqqHAFH7IYB1Wd7hj_fweXWwdmav4fWOITMT3Ey9nlNSZ58v_5-9-LrLvvqLXYH20yoNft40J-2CdAuaOKQUwaoxurWOPxQlajN2ajt2Kn-72oyd4tnz4vaH53YN3R_H3ZxlgG2BlI9CD_G-Bf-u-gvPwNrS</recordid><startdate>20201001</startdate><enddate>20201001</enddate><creator>Shah, 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Sciences</topic><topic>Biomedicine</topic><topic>Cancer Research</topic><topic>CD19 antigen</topic><topic>CD20 antigen</topic><topic>Chimeric antigen receptors</topic><topic>Chronic lymphocytic leukemia</topic><topic>Cryopreservation</topic><topic>Diseases</topic><topic>Dose-Response Relationship, Immunologic</topic><topic>Down-regulation</topic><topic>Effectiveness</topic><topic>Feasibility</topic><topic>Female</topic><topic>Health aspects</topic><topic>Health services</topic><topic>Humans</topic><topic>Immunotherapy</topic><topic>Immunotherapy, Adoptive - methods</topic><topic>Infectious Diseases</topic><topic>Letter</topic><topic>Leukemia</topic><topic>Leukemia, B-Cell - immunology</topic><topic>Leukemia, B-Cell - pathology</topic><topic>Leukemia, B-Cell - therapy</topic><topic>Lymphatic leukemia</topic><topic>Lymphocyte Count</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Lymphoma</topic><topic>Lymphoma, B-Cell - immunology</topic><topic>Lymphoma, B-Cell - 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Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><jtitle>Nature medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shah, Nirav N.</au><au>Johnson, Bryon D.</au><au>Schneider, Dina</au><au>Zhu, Fenlu</au><au>Szabo, Aniko</au><au>Keever-Taylor, Carolyn A.</au><au>Krueger, Winfried</au><au>Worden, Andrew A.</au><au>Kadan, Michael J.</au><au>Yim, Sharon</au><au>Cunningham, Ashley</au><au>Hamadani, Mehdi</au><au>Fenske, Timothy S.</au><au>Dropulić, Boro</au><au>Orentas, Rimas</au><au>Hari, Parameswaran</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial</atitle><jtitle>Nature medicine</jtitle><stitle>Nat Med</stitle><addtitle>Nat Med</addtitle><date>2020-10-01</date><risdate>2020</risdate><volume>26</volume><issue>10</issue><spage>1569</spage><epage>1575</epage><pages>1569-1575</pages><issn>1078-8956</issn><eissn>1546-170X</eissn><abstract>Chimeric antigen receptor (CAR) T cells targeting CD19 are a breakthrough treatment for relapsed, refractory B cell malignancies
1
–
5
. Despite impressive outcomes, relapse with CD19
−
disease remains a challenge. We address this limitation through a first-in-human trial of bispecific anti-CD20, anti-CD19 (LV20.19) CAR T cells for relapsed, refractory B cell malignancies. Adult patients with B cell non-Hodgkin lymphoma or chronic lymphocytic leukemia were treated on a phase 1 dose escalation and expansion trial (
NCT03019055
) to evaluate the safety of 4-1BB–CD3ζ LV20.19 CAR T cells and the feasibility of on-site manufacturing using the CliniMACS Prodigy system. CAR T cell doses ranged from 2.5 × 10
5
–2.5 × 10
6
cells per kg. Cell manufacturing was set at 14 d with the goal of infusing non-cryopreserved LV20.19 CAR T cells. The target dose of LV20.19 CAR T cells was met in all CAR-naive patients, and 22 patients received LV20.19 CAR T cells on protocol. In the absence of dose-limiting toxicity, a dose of 2.5 × 10
6
cells per kg was chosen for expansion. Grade 3–4 cytokine release syndrome occurred in one (5%) patient, and grade 3–4 neurotoxicity occurred in three (14%) patients. Eighteen (82%) patients achieved an overall response at day 28, 14 (64%) had a complete response, and 4 (18%) had a partial response. The overall response rate to the dose of 2.5 × 10
6
cells per kg with non-cryopreserved infusion (
n
= 12) was 100% (complete response, 92%; partial response, 8%). Notably, loss of the CD19 antigen was not seen in patients who relapsed or experienced treatment failure. In conclusion, on-site manufacturing and infusion of non-cryopreserved LV20.19 CAR T cells were feasible and therapeutically safe, showing low toxicity and high efficacy. Bispecific CARs may improve clinical responses by mitigating target antigen downregulation as a mechanism of relapse.
A new bispecific CAR T cell product targeting the CD20 and CD19 antigens demonstrates an excellent safety profile and high clinical efficacy in patients with B cell non-Hodgkin lymphoma and chronic lymphocytic leukemia.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>33020647</pmid><doi>10.1038/s41591-020-1081-3</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0002-8129-0614</orcidid><orcidid>https://orcid.org/0000-0002-3861-7677</orcidid><orcidid>https://orcid.org/0000-0002-3085-6876</orcidid><orcidid>https://orcid.org/0000-0001-5372-510X</orcidid><orcidid>https://orcid.org/0000-0001-6442-1320</orcidid><orcidid>https://orcid.org/0000-0002-4336-1071</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1078-8956 |
| ispartof | Nature medicine, 2020-10, Vol.26 (10), p.1569-1575 |
| issn | 1078-8956 1546-170X |
| language | eng |
| recordid | cdi_proquest_journals_2828066457 |
| source | MEDLINE; Springer Nature - Complete Springer Journals; Nature Journals Online |
| subjects | 631/250/251 631/67/1990/283 631/67/1990/291 Adult Aged Antigens Antigens, CD19 - immunology Antigens, CD20 - immunology B cells Biomedical and Life Sciences Biomedicine Cancer Research CD19 antigen CD20 antigen Chimeric antigen receptors Chronic lymphocytic leukemia Cryopreservation Diseases Dose-Response Relationship, Immunologic Down-regulation Effectiveness Feasibility Female Health aspects Health services Humans Immunotherapy Immunotherapy, Adoptive - methods Infectious Diseases Letter Leukemia Leukemia, B-Cell - immunology Leukemia, B-Cell - pathology Leukemia, B-Cell - therapy Lymphatic leukemia Lymphocyte Count Lymphocytes Lymphocytes T Lymphoma Lymphoma, B-Cell - immunology Lymphoma, B-Cell - pathology Lymphoma, B-Cell - therapy Male Malignancy Manufacturing Metabolic Diseases Methods Middle Aged Molecular Medicine Neurosciences Neurotoxicity Non-Hodgkin's lymphoma Onsite Patients Physiological aspects Receptors, Antigen, T-Cell - immunology Receptors, Chimeric Antigen - immunology Recurrence Relapse T cells T-Lymphocytes - cytology T-Lymphocytes - immunology T-Lymphocytes - metabolism T-Lymphocytes - transplantation Toxicity |
| title | Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-01T21%3A35%3A44IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Bispecific%20anti-CD20,%20anti-CD19%20CAR%20T%20cells%20for%20relapsed%20B%20cell%20malignancies:%20a%20phase%201%20dose%20escalation%20and%20expansion%20trial&rft.jtitle=Nature%20medicine&rft.au=Shah,%20Nirav%20N.&rft.date=2020-10-01&rft.volume=26&rft.issue=10&rft.spage=1569&rft.epage=1575&rft.pages=1569-1575&rft.issn=1078-8956&rft.eissn=1546-170X&rft_id=info:doi/10.1038/s41591-020-1081-3&rft_dat=%3Cgale_proqu%3EA637731742%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2828066457&rft_id=info:pmid/33020647&rft_galeid=A637731742&rfr_iscdi=true |