{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T19:19:28Z","timestamp":1793992768613,"version":"4.8.0"},"reference-count":44,"publisher":"American Society of Hematology","issue":"5","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,8,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Remission durability following single-antigen targeted chimeric antigen receptor (CAR) T-cells is limited by antigen modulation, which may be overcome with combinatorial targeting. Building upon our experiences targeting CD19 and CD22 in B-cell acute lymphoblastic leukemia (B-ALL), we report on our phase 1 dose-escalation study of a novel murine stem cell virus (MSCV)-CD19\/CD22-4-1BB bivalent CAR T-cell (CD19.22.BB\u03b6) for children and young adults (CAYA) with B-cell malignancies. Primary objectives included toxicity and dose finding. Secondary objectives included response rates and relapse-free survival (RFS). Biologic correlatives included laboratory investigations, CAR T-cell expansion and cytokine profiling. Twenty patients, ages 5.4 to 34.6 years, with B-ALL received CD19.22.BB\u03b6. The complete response (CR) rate was 60% (12 of 20) in the full cohort and 71.4% (10 of 14) in CAR-na\u00efve patients. Ten (50%) developed cytokine release syndrome (CRS), with 3 (15%) having \u2265 grade 3 CRS and only 1 experiencing neurotoxicity (grade 3). The 6- and 12-month RFS in those achieving CR was 80.8% (95% confidence interval [CI]: 42.4%-94.9%) and 57.7% (95% CI: 22.1%-81.9%), respectively. Limited CAR T-cell expansion and persistence of MSCV-CD19.22.BB\u03b6 compared with EF1\u03b1-CD22.BB\u03b6 prompted laboratory investigations comparing EF1\u03b1 vs MSCV promoters, which did not reveal major differences. Limited CD22 targeting with CD19.22.BB\u03b6, as evaluated by ex vivo cytokine secretion and leukemia eradication in humanized mice, led to development of a novel bicistronic CD19.28\u03b6\/CD22.BB\u03b6 construct with enhanced cytokine production against CD22. With demonstrated safety and efficacy of CD19.22.BB\u03b6 in a heavily pretreated CAYA B-ALL cohort, further optimization of combinatorial antigen targeting serves to overcome identified limitations (www.clinicaltrials.gov #NCT03448393).<\/jats:p>","DOI":"10.1182\/blood.2022015795","type":"journal-article","created":{"date-parts":[[2022,5,23]],"date-time":"2022-05-23T15:55:25Z","timestamp":1653321325000},"page":"451-463","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":148,"title":["CD19\/22 CAR T cells in children and young adults with B-ALL: phase 1 results and development of a novel bicistronic CAR"],"prefix":"10.1182","volume":"140","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8692-8034","authenticated-orcid":false,"given":"Haneen","family":"Shalabi","sequence":"first","affiliation":[{"name":"1Pediatric Oncology Branch 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MD;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5513-1233","authenticated-orcid":false,"given":"John A.","family":"Ligon","sequence":"additional","affiliation":[{"name":"1Pediatric Oncology Branch and"},{"name":"3Division of Hematology\/Oncology, Department of Pediatrics, University of Florida, Gainesville, FL;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Silbert","sequence":"additional","affiliation":[{"name":"1Pediatric Oncology Branch and"},{"name":"4Center for Cancer and Blood Disorders, Children\u2019s National Hospital, Washington, DC;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kniya","family":"D\u00e9D\u00e9","sequence":"additional","affiliation":[{"name":"1Pediatric Oncology Branch 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