{"doi":"10.1136/jitc-2025-011549","title":"CD22-targeted chimeric antigen receptor-modified T cells for children and adults with relapse of B-cell acute lymphoblastic leukemia after CD19-directed immunotherapy","abstract":"<jats:sec>\n                    <jats:title>Background</jats:title>\n                    <jats:p>Relapse of B-cell acute lymphoblastic leukemia (B-ALL) with CD19-antigen loss after CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has a dismal prognosis. Novel immunotherapeutic strategies for this patient population are urgently needed.</jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods</jats:title>\n                    <jats:p>We tested a novel, fully human anti-CD22/4-1BB CAR T-cell construct, CART22-65s, in parallel phase I studies for pediatric and adult B-ALL. After lymphodepletion, CART22-65s was infused using a 3-day fractionated dosing scheme, allowing for omission of the second and third doses in cases of early cytokine release syndrome (CRS).</jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>Results</jats:title>\n                    <jats:p>Twenty-two patients, all with relapse after prior CD19-directed immunotherapy, were enrolled. Of 19 infused patients (pediatric, n=17; adult, n=2), 14 (74%) achieved a complete remission (CR), including 4 of 6 (67%) patients refractory to prior inotuzumab. Five of 14 patients in a CR proceeded to consolidative hematopoietic cell transplantation (HCT). With a median follow-up of 38 months, the 12-month relapse-free survival rate was 38.4% (95% CI 19.3% to 76.5%) and overall survival rate was 52.6% (95% CI 34.3% to 80.6%). Two patients received additional CART22-65s treatments for subsequent CD22-positive relapses; one achieved another CR. All CRS (n=17, 89%) and neurotoxicity (n=4, 21%) events after initial infusion were grades 1–2. The only grade 3 CRS/neurotoxicity and the only high-grade immune effector cell-associated hemophagocytic lymphohistocytosis-like syndrome occurred in the retreatment setting. In vivo cellular kinetic data revealed robust CART22-65s proliferation by quantitative PCR peaking at a median of 20 days postinfusion, with the cells persisting out to month 42 in one patient who achieved a long-term remission with CART22-65s alone.</jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions</jats:title>\n                    <jats:p>The favorable safety profile and high remission rates in exceedingly refractory B-ALL support the continued development of CART22-65s but also highlight the need to use the product in combination with HCT or other novel strategies.</jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration numbers</jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT02650414\">NCT02650414</jats:ext-link>\n                      and\n                      <jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT03620058\">NCT03620058</jats:ext-link>\n                      .\n                    </jats:p>\n                  </jats:sec>","journal":"Journal for ImmunoTherapy of Cancer","year":2025,"id":623689,"datarank":0.6276629247972203,"base_score":3.091042453358316,"endowment":3.091042453358316,"self_citation_contribution":0.4636563680037475,"citation_network_contribution":0.1640065567934728,"self_endowment_contribution":0.4636563680037475,"citer_contribution":0.1640065567934728,"corpus_percentile":null,"corpus_rank":null,"citation_count":21,"citer_count":17,"citers_with_citation_signal":7,"citers_with_endowment":7,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1611957,"name":"Amanda M DiNofia","orcid":null,"position":1,"is_corresponding":false},{"id":1167082,"name":"Yimei Li","orcid":"0000-0003-0774-4515","position":2,"is_corresponding":false},{"id":260210,"name":"Caroline Diorio","orcid":"0000-0002-8005-3836","position":3,"is_corresponding":false},{"id":632639,"name":"Hongyan Liu","orcid":"0000-0001-8215-2160","position":4,"is_corresponding":false},{"id":295574,"name":"Gerald Wertheim","orcid":"0000-0002-1585-846X","position":5,"is_corresponding":false},{"id":1611962,"name":"Joseph A Fraietta","orcid":null,"position":6,"is_corresponding":false},{"id":759999,"name":"Vanessa Gonzalez","orcid":"0000-0003-3603-7457","position":7,"is_corresponding":false},{"id":325455,"name":"Gabriela Plesa","orcid":"0000-0002-4279-5943","position":8,"is_corresponding":false},{"id":1611964,"name":"Donald L Siegel","orcid":null,"position":9,"is_corresponding":false},{"id":1611966,"name":"Emma Iannone","orcid":null,"position":10,"is_corresponding":false},{"id":1611968,"name":"Laura Shinehouse","orcid":null,"position":11,"is_corresponding":false},{"id":1611970,"name":"Jennifer L Brogdon","orcid":null,"position":12,"is_corresponding":false},{"id":1059745,"name":"Clare Taylor","orcid":"0000-0002-6181-1400","position":13,"is_corresponding":false},{"id":1611971,"name":"Julie K Jadlowsky","orcid":null,"position":14,"is_corresponding":false},{"id":1611972,"name":"Elizabeth O Hexner","orcid":null,"position":15,"is_corresponding":false},{"id":1238748,"name":"Boris Engels","orcid":"0000-0001-9682-2954","position":16,"is_corresponding":false},{"id":633611,"name":"Diane Baniewicz","orcid":null,"position":17,"is_corresponding":false},{"id":632641,"name":"Colleen Callahan","orcid":"0000-0001-6419-3620","position":18,"is_corresponding":false},{"id":256650,"name":"Marco Ruella","orcid":"0000-0003-4301-5811","position":19,"is_corresponding":false},{"id":85409,"name":"Richard Aplenc","orcid":"0000-0001-7482-5644","position":20,"is_corresponding":false},{"id":632637,"name":"Allison Barz Leahy","orcid":"0000-0002-1368-4064","position":21,"is_corresponding":false},{"id":1611973,"name":"Susan E McClory","orcid":null,"position":22,"is_corresponding":false},{"id":1611974,"name":"Susan R Rheingold","orcid":null,"position":23,"is_corresponding":false},{"id":632642,"name":"Lisa Wray","orcid":"0000-0003-0012-9739","position":24,"is_corresponding":false},{"id":1611975,"name":"Carl H June","orcid":null,"position":25,"is_corresponding":false},{"id":632643,"name":"Shannon L. Maude","orcid":"0000-0003-2210-8736","position":26,"is_corresponding":false},{"id":1611976,"name":"Noelle V Frey","orcid":null,"position":27,"is_corresponding":false},{"id":1611977,"name":"Stephan A Grupp","orcid":null,"position":28,"is_corresponding":false},{"id":623304,"name":"Regina M. Myers","orcid":"0000-0002-2542-2061","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"CD22-targeted chimeric antigen receptor-modified T cells for children and adults with relapse of B-cell acute lymphoblastic leukemia after CD19-directed immunotherapy","abstract":"<jats:sec>\n                    <jats:title>Background</jats:title>\n                    <jats:p>Relapse of B-cell acute lymphoblastic leukemia (B-ALL) with CD19-antigen loss after CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has a dismal prognosis. Novel immunotherapeutic strategies for this patient population are urgently needed.</jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods</jats:title>\n                    <jats:p>We tested a novel, fully human anti-CD22/4-1BB CAR T-cell construct, CART22-65s, in parallel phase I studies for pediatric and adult B-ALL. After lymphodepletion, CART22-65s was infused using a 3-day fractionated dosing scheme, allowing for omission of the second and third doses in cases of early cytokine release syndrome (CRS).</jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>Results</jats:title>\n                    <jats:p>Twenty-two patients, all with relapse after prior CD19-directed immunotherapy, were enrolled. Of 19 infused patients (pediatric, n=17; adult, n=2), 14 (74%) achieved a complete remission (CR), including 4 of 6 (67%) patients refractory to prior inotuzumab. Five of 14 patients in a CR proceeded to consolidative hematopoietic cell transplantation (HCT). With a median follow-up of 38 months, the 12-month relapse-free survival rate was 38.4% (95% CI 19.3% to 76.5%) and overall survival rate was 52.6% (95% CI 34.3% to 80.6%). Two patients received additional CART22-65s treatments for subsequent CD22-positive relapses; one achieved another CR. All CRS (n=17, 89%) and neurotoxicity (n=4, 21%) events after initial infusion were grades 1–2. The only grade 3 CRS/neurotoxicity and the only high-grade immune effector cell-associated hemophagocytic lymphohistocytosis-like syndrome occurred in the retreatment setting. In vivo cellular kinetic data revealed robust CART22-65s proliferation by quantitative PCR peaking at a median of 20 days postinfusion, with the cells persisting out to month 42 in one patient who achieved a long-term remission with CART22-65s alone.</jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions</jats:title>\n                    <jats:p>The favorable safety profile and high remission rates in exceedingly refractory B-ALL support the continued development of CART22-65s but also highlight the need to use the product in combination with HCT or other novel strategies.</jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration numbers</jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT02650414\">NCT02650414</jats:ext-link>\n                      and\n                      <jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT03620058\">NCT03620058</jats:ext-link>\n                      .\n                    </jats:p>\n                  </jats:sec>","is_dataset_classified":null,"base_score":3.091042453358316,"endowment":3.091042453358316,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"40246579","pmcid":"PMC12007026","openalex_id":"https://openalex.org/W4409535413","authors":[],"funders":[{"funder_name":"National Cancer Institute","grant_id":"5-K08-CA-277013","title":null},{"funder_name":"National Cancer Institute","grant_id":"5-P01-CA-214278","title":null},{"funder_name":"NCI NIH HHS","grant_id":"K08 CA286762","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"R01 HL178849","title":null},{"funder_name":"NCI NIH HHS","grant_id":"P01 CA214278","title":null},{"funder_name":"FDA HHS","grant_id":"R01 FD008168","title":null},{"funder_name":"NCI NIH HHS","grant_id":"K08 CA277013","title":null},{"funder_name":"NCI NIH HHS","grant_id":"R37 CA262362","title":null},{"funder_name":"National Institutes of Health","grant_id":"5K08CA277013-02","title":"Optimizing outcomes for children and young adults with relapse of B-cell acute lymphoblastic leukemia after CD19-targeted chimeric antigen receptor T-cell therapy"},{"funder_name":"National Institutes of Health","grant_id":"3P01CA214278-02S1","title":"Enhancing Chimeric Antigen Receptor T Cell Therapies for Hematologic Malignancies: Beyond CART 19"},{"funder_name":"Curing Kids Cancer","grant_id":"","title":null},{"funder_name":"American Society of Hematology","grant_id":"","title":null},{"funder_name":"Susan S. and Stephen P. Kelly Center for Pediatric Cancer Immunotherapy at Children’s Hospital of Philadelphia","grant_id":"","title":null},{"funder_name":"Emily Whitehead Foundation","grant_id":"","title":null}],"total_grants":14,"fwci":10.2885,"citation_percentile":0.98755814,"influential_citations":0,"citation_trend":[{"year":2025,"count":8},{"year":2026,"count":13}],"oa_status":"gold","license":"CC BY NC","oa_locations":[{"url":"https://doi.org/10.1136/jitc-2025-011549","host_type":"journal"},{"url":"https://doi.org/10.1136/jitc-2025-011549","host_type":"publisher"},{"url":"https://syndication.highwire.org/content/doi/10.1136/jitc-2025-011549","host_type":"publisher"},{"url":"https://pubmed.ncbi.nlm.nih.gov/40246579","host_type":"repository"},{"url":"https://doaj.org/article/856ceefb3270486981949d35e38f234b","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/12007026","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC12007026","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC12007026?pdf=render","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.1136/jitc-2025-011549","host_type":""}],"fields_of_study":["CAR-T cell therapy research","Acute Lymphoblastic Leukemia research","Lymphoma Diagnosis and Treatment","03 medical and health sciences","0302 clinical medicine"],"mesh_terms":["Receptors, Chimeric Antigen","Adolescent","Adult","Child","Child, Preschool","Female","Humans","Immunotherapy","Male","Middle Aged","Recurrence","T-Lymphocytes","Precursor B-Cell Lymphoblastic Leukemia-Lymphoma","Immunotherapy, Adoptive","Antigens, CD19","Sialic Acid Binding Ig-like Lectin 2","Young Adult"],"keywords":["Medicine","Cytokine release syndrome","Chimeric antigen receptor","Immunotherapy","CD19","Internal medicine","Antigen","Immunology","Population","T cell","Oncology","Immune system","Leukemia","Relapse","Chimeric Antigen Receptor - Car","Male","Adult","Receptors, Chimeric Antigen","Adolescent","Sialic Acid Binding Ig-like Lectin 2","T-Lymphocytes","Antigens, CD19","Neoplasms. Tumors. Oncology. Including cancer and carcinogens","Clinical Cancer Immunotherapy","Middle Aged","Immunotherapy, Adoptive","Young Adult","Recurrence","Child, Preschool","Precursor B-Cell Lymphoblastic Leukemia-Lymphoma","Humans","Female","Child","RC254-282"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"nct"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-04T00:56:18.835704Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}