{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T10:31:14Z","timestamp":1794047474469,"version":"4.8.0"},"reference-count":57,"publisher":"Ferrata Storti Foundation (Haematologica)","issue":"6","license":[{"start":{"date-parts":[[2024,5,10]],"date-time":"2024-05-10T00:00:00Z","timestamp":1715299200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["haematol"],"abstract":"<jats:p>Chimeric antigen receptor (CAR) T-cell therapy has emerged as a breakthrough cancer therapy over the past decade. Remarkable outcomes in B-cell lymphoproliferative disorders and multiple myeloma have been reported in both pivotal trials and real-word studies. Traditionally, the use of a patient\u2019s own (autologous) T cells to manufacture CAR products has been the standard practice. Nevertheless, this approach has some drawbacks, including manufacturing delays, dependence on the functional fitness of the patient\u2019s T cells, which can be compromised by both the disease and prior therapies, and contamination of the product with blasts. A promising alternative is offered by the development of allogeneic CAR-cell products. This approach has the potential to yield more efficient drug products and enables the use of effector cells with negligible alloreactive potential and a significant CAR-independent antitumor activity through their innate receptors (i.e., natural killer cells, \u03b3\u03b4 T cells and cytokine induced killer cells). In addition, recent advances in genome editing tools offer the potential to overcome the primary challenges associated with allogeneic CAR T-cell products, namely graft-versus-host disease and host allo-rejection, generating universal, off-the-shelf products. In this review, we summarize the current pre-clinical and clinical approaches based on allogeneic CAR T cells, as well as on alternative effector cells, which represent exciting opportunities for multivalent approaches and optimized antitumor activity.<\/jats:p>","DOI":"10.3324\/haematol.2023.284604","type":"journal-article","created":{"date-parts":[[2024,6,1]],"date-time":"2024-06-01T03:43:41Z","timestamp":1717213421000},"page":"1689-1699","source":"Crossref","is-referenced-by-count":18,"title":["Allogeneic chimeric antigen receptor T cells for children with relapsed\/refractory B-cell precursor acute lymphoblastic leukemia"],"prefix":"10.3324","volume":"109","author":[{"given":"Franco","family":"Locatelli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Del Bufalo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Concetta","family":"Quintarelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1856","published-online":{"date-parts":[[2024,5,10]]},"reference":[{"key":"61444","doi-asserted-by":"crossref","unstructured":"Maude SL, Laetsch TW, Buechner J. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018; 378(5):439-448.","DOI":"10.1056\/NEJMoa1709866"},{"key":"61445","doi-asserted-by":"crossref","unstructured":"Laetsch TW, Maude SL, Rives S. Three-year update of tisagenlecleucel in pediatric and young adult patients with relapsed\/refractory acute lymphoblastic leukemia in the ELIANA trial. J Clin Oncol. 2023; 41(9):1664-1669.","DOI":"10.1200\/JCO.22.00642"},{"key":"61446","doi-asserted-by":"crossref","unstructured":"Pasquini MC, Hu ZH, Curran K. Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma. Blood Adv. 2020; 4(21):5414-5424.","DOI":"10.1182\/bloodadvances.2020003092"},{"key":"61447","doi-asserted-by":"crossref","unstructured":"Bader P, Rossig C, Hutter M. CD19 CAR T cells are an effective therapy for posttransplant relapse in patients with B-lineage ALL: real-world data from Germany. Blood Adv. 2023; 7(11):2436-2448.","DOI":"10.1182\/bloodadvances.2022008981"},{"key":"61448","doi-asserted-by":"crossref","unstructured":"Schultz LM, Baggott C, Prabhu S. Disease burden affects outcomes in pediatric and young adult B-cell lymphoblastic leukemia after commercial tisagenlecleucel: a Pediatric Real-World Chimeric Antigen Receptor Consortium report. J Clin Oncol. 2022; 40(9):945-955.","DOI":"10.1200\/JCO.20.03585"},{"key":"61449","doi-asserted-by":"crossref","unstructured":"Leahy AB, Devine KJ, Li Y. Impact of high-risk cytogenetics on outcomes for children and young adults receiving CD19-directed CAR T-cell therapy. Blood. 2022; 139(14):2173-2185.","DOI":"10.1182\/blood.2021012727"},{"key":"61450","doi-asserted-by":"crossref","unstructured":"Moskop A, Pommert L, Baggott C. Real-world use of tisagenlecleucel in infant acute lymphoblastic leukemia. Blood Adv. 2022; 6(14):4251-4255.","DOI":"10.1182\/bloodadvances.2021006393"},{"key":"61451","doi-asserted-by":"crossref","unstructured":"Ghorashian S, Jacoby E, De Moerloose B. Tisagenlecleucel therapy for relapsed or refractory B-cell acute lymphoblastic leukaemia in infants and children younger than 3 years of age at screening: an international, multicentre, retrospective cohort study. Lancet Haematol. 2022; 9(10):e766-e775.","DOI":"10.1016\/S2352-3026(22)00225-3"},{"key":"61452","doi-asserted-by":"crossref","unstructured":"Fabrizio VA, Phillips CL, Lane A. Tisagenlecleucel outcomes in relapsed\/refractory extramedullary ALL: a Pediatric Real World CAR Consortium report. Blood Adv. 2022; 6(2):600-610.","DOI":"10.1182\/bloodadvances.2021005564"},{"key":"61453","doi-asserted-by":"crossref","unstructured":"Leahy AB, Newman H, Li Y. CD19-targeted chimeric antigen receptor T-cell therapy for CNS relapsed or refractory acute lymphocytic leukaemia: a post-hoc analysis of pooled data from five clinical trials. Lancet Haematol. 2021; 8(10):e711-e722.","DOI":"10.1016\/S2352-3026(21)00238-6"},{"key":"61454","doi-asserted-by":"crossref","unstructured":"Jacoby E, Ghorashian S, Vormoor B. CD19 CAR T-cells for pediatric relapsed acute lymphoblastic leukemia with active CNS involvement: a retrospective international study. Leukemia. 2022; 36(6):1525-1532.","DOI":"10.1038\/s41375-022-01546-9"},{"key":"61455","doi-asserted-by":"crossref","unstructured":"Qi Y, Zhao M, Hu Y. Efficacy and safety of CD19-specific CAR T cell-based therapy in B-cell acute lymphoblastic leukemia patients with CNSL. Blood. 2022; 139(23):3376-3386.","DOI":"10.1182\/blood.2021013733"},{"key":"61456","doi-asserted-by":"crossref","unstructured":"Hutt D, Bielorai B, Baturov B. Feasibility of leukapheresis for CAR T-cell production in heavily pre-treated pediatric patients. Transfus Apher Sci. 2020; 59(4):102769.","DOI":"10.1016\/j.transci.2020.102769"},{"key":"61457","doi-asserted-by":"crossref","unstructured":"Shalabi H, Shah NN. CD19 CAR T cells for infants and young children. Lancet Haematol. 2022; 9(10):e712-e714.","DOI":"10.1016\/S2352-3026(22)00258-7"},{"key":"61458","doi-asserted-by":"crossref","unstructured":"Shah NN, Fry TJ. Mechanisms of resistance to CAR T cell therapy. Nat Rev Clin Oncol. 2019; 16(6):372-385.","DOI":"10.1038\/s41571-019-0184-6"},{"key":"61459","doi-asserted-by":"crossref","unstructured":"Stroncek DF, Ren J, Lee DW. Myeloid cells in peripheral blood mononuclear cell concentrates inhibit the expansion of chimeric antigen receptor T cells. Cytotherapy. 2016; 18(7):893-901.","DOI":"10.1016\/j.jcyt.2016.04.003"},{"key":"61460","doi-asserted-by":"crossref","unstructured":"De Veirman K, Van Valckenborgh E, Lahmar Q. Myeloid-derived suppressor cells as therapeutic target in hematological malignancies. Front Oncol. 2014; 4:349.","DOI":"10.3389\/fonc.2014.00349"},{"key":"61461","doi-asserted-by":"crossref","unstructured":"Ruella M, Xu J, Barrett DM. Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell. Nat Med. 2018; 24(10):1499-1503.","DOI":"10.1038\/s41591-018-0201-9"},{"key":"61462","doi-asserted-by":"crossref","unstructured":"van der Leun AM, Thommen DS, Schumacher TN. CD8(+) T cell states in human cancer: insights from single-cell analysis. Nat Rev Cancer. 2020; 20(4):218-232.","DOI":"10.1038\/s41568-019-0235-4"},{"key":"61463","doi-asserted-by":"crossref","unstructured":"Singh N, Perazzelli J, Grupp SA. Early memory phenotypes drive T cell proliferation in patients with pediatric malignancies. Sci Transl Med. 2016; 8(320):320ra3.","DOI":"10.1126\/scitranslmed.aad5222"},{"key":"61464","doi-asserted-by":"crossref","unstructured":"Daudt L, Maccario R, Locatelli F. Interleukin-15 favors the expansion of central memory CD8+ T cells in ex vivo generated, antileukemia human cytotoxic T lymphocyte lines. J Immunother. 2008; 31(4):385-393.","DOI":"10.1097\/CJI.0b013e31816b1092"},{"key":"61465","doi-asserted-by":"crossref","unstructured":"Arcangeli S, Bove C, Mezzanotte C. CAR T cell manufacturing from naive\/stem memory T lymphocytes enhances antitumor responses while curtailing cytokine release syndrome. J Clin Invest. 2022; 132(12):e150807.","DOI":"10.1172\/JCI150807"},{"key":"61466","doi-asserted-by":"crossref","unstructured":"Cruz CR, Micklethwaite KP, Savoldo B. Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study. Blood. 2013; 122(17):2965-2973.","DOI":"10.1182\/blood-2013-06-506741"},{"key":"61467","doi-asserted-by":"crossref","unstructured":"Kochenderfer JN, Dudley ME, Carpenter RO. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood. 2013; 122(25):4129-4139.","DOI":"10.1182\/blood-2013-08-519413"},{"key":"61468","doi-asserted-by":"crossref","unstructured":"Brudno JN, Somerville RP, Shi V. Allogeneic T cells that express an anti-CD19 chimeric antigen receptor induce remissions of B-cell malignancies that progress after allogeneic hematopoietic stem-cell transplantation without causing graft-versus-host disease. J Clin Oncol. 2016; 34(10):1112-1121.","DOI":"10.1200\/JCO.2015.64.5929"},{"key":"61469","doi-asserted-by":"crossref","unstructured":"Dai H, Zhang W, Li X. Tolerance and efficacy of autologous or donor-derived T cells expressing CD19 chimeric antigen receptors in adult B-ALL with extramedullary leukemia. Oncoimmunology. 2015; 4(11):e1027469.","DOI":"10.1080\/2162402X.2015.1027469"},{"key":"61470","doi-asserted-by":"crossref","unstructured":"Chen Y, Cheng Y, Suo P. Donor-derived CD19-targeted T cell infusion induces minimal residual disease-negative remission in relapsed B-cell acute lymphoblastic leukaemia with no response to donor lymphocyte infusions after haploidentical haematopoietic stem cell transplantation. Br J Haematol. 2017; 179(4):598-605.","DOI":"10.1111\/bjh.14923"},{"key":"61471","doi-asserted-by":"crossref","unstructured":"Yan CH, Liu DH, Xu LP. Modified donor lymphocyte infusion-associated acute graft-versus-host disease after haploidentical T-cell-replete hematopoietic stem cell transplantation: incidence and risk factors. Clin Transplant. 2012; 26(6):868-876.","DOI":"10.1111\/j.1399-0012.2012.01618.x"},{"key":"61472","doi-asserted-by":"crossref","unstructured":"Kebriaei P, Singh H, Huls MH. Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells. J Clin Invest. 2016; 126(9):3363-3376.","DOI":"10.1172\/JCI86721"},{"key":"61473","doi-asserted-by":"crossref","unstructured":"Zhang C, Wang XQ, Zhang RL. Donor-derived CD19 CAR-T cell therapy of relapse of CD19-positive B-ALL post allotransplant. Leukemia. 2021; 35(6):1563-1570.","DOI":"10.1038\/s41375-020-01056-6"},{"key":"61474","doi-asserted-by":"crossref","unstructured":"Del Bufalo F, Becilli M, Rosignoli C. Allogeneic, donor-derived, second-generation, CD19-directed CAR-T cells for the treatment of pediatric relapsed\/refractory BCP-ALL. Blood. 2023; 142(2):146-157.","DOI":"10.1182\/blood.2023020023"},{"key":"61475","doi-asserted-by":"crossref","unstructured":"Opelz G, Dohler B. Effect of human leukocyte antigen compatibility on kidney graft survival: comparative analysis of two decades. Transplantation. 2007; 84(2):137-143.","DOI":"10.1097\/01.tp.0000269725.74189.b9"},{"key":"61476","doi-asserted-by":"crossref","unstructured":"Kurtzberg J, Prasad VK, Carter SL. Results of the Cord Blood Transplantation Study (COBLT): clinical outcomes of unrelated donor umbilical cord blood transplantation in pediatric patients with hematologic malignancies. Blood. 2008; 112(10):4318-4327.","DOI":"10.1182\/blood-2007-06-098020"},{"key":"61477","doi-asserted-by":"crossref","unstructured":"Depil S, Duchateau P, Grupp SA. \u2018Off-the-shelf\u2019 allogeneic CAR T cells: development and challenges. Nat Rev Drug Discov. 2020; 19(3):185-199.","DOI":"10.1038\/s41573-019-0051-2"},{"key":"61478","doi-asserted-by":"crossref","unstructured":"Qasim W, Zhan H, Samarasinghe S. Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Sci Transl Med. 2017; 9(374):eaaj2013.","DOI":"10.1126\/scitranslmed.aaj2013"},{"key":"61479","doi-asserted-by":"crossref","unstructured":"Benjamin R, Graham C, Yallop D. Genome-edited, donor-derived allogeneic anti-CD19 chimeric antigen receptor T cells in paediatric and adult B-cell acute lymphoblastic leukaemia: results of two phase 1 studies. Lancet. 2020; 396(10266):1885-1894.","DOI":"10.1016\/S0140-6736(20)32334-5"},{"key":"61480","doi-asserted-by":"crossref","unstructured":"Ottaviano G, Georgiadis C, Gkazi SA. Phase 1 clinical trial of CRISPR-engineered CAR19 universal T cells for treatment of children with refractory B cell leukemia. Sci Transl Med. 2022; 14(668):eabq3010.","DOI":"10.1126\/scitranslmed.abq3010"},{"key":"61481","doi-asserted-by":"crossref","unstructured":"Hu Y, Zhou Y, Zhang M. CRISPR\/Cas9-engineered universal CD19\/CD22 dual-targeted CAR-T cell therapy for relapsed\/ refractory B-cell acute lymphoblastic leukemia. Clin Cancer Res. 2021; 27(10):2764-2772.","DOI":"10.1158\/1078-0432.CCR-20-3863"},{"key":"61482","doi-asserted-by":"crossref","unstructured":"Themeli M, Kloss CC, Ciriello G. Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy. Nat Biotechnol. 2013; 31(10):928-933.","DOI":"10.1038\/nbt.2678"},{"key":"61483","doi-asserted-by":"crossref","unstructured":"van der Stegen SJC, Lindenbergh PL, Petrovic RM. Generation of T-cell-receptor-negative CD8ap-positive CAR T cells from T-cell-derived induced pluripotent stem cells. Nat Biomed Eng. 2022; 6(11):1284-1297.","DOI":"10.1038\/s41551-022-00915-0"},{"key":"61484","doi-asserted-by":"crossref","unstructured":"Ueda T, Shiina S, Iriguchi S. Optimization of the proliferation and persistency of CAR T cells derived from human induced pluripotent stem cells. Nat Biomed Eng. 2023; 7(1):24-37.","DOI":"10.1038\/s41551-022-00969-0"},{"key":"61485","doi-asserted-by":"crossref","unstructured":"Wang Z, McWilliams-Koeppen HP, Reza H. 3D-organoid culture supports differentiation of human CAR(+) iPSCs into highly functional CAR T cells. Cell Stem Cell. 2022; 29(4):515-527.e8.","DOI":"10.1016\/j.stem.2022.02.009"},{"key":"61486","doi-asserted-by":"crossref","unstructured":"Liu E, Marin D, Banerjee P. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N Engl J Med. 2020; 382(6):545-553.","DOI":"10.1056\/NEJMoa1910607"},{"key":"61487","doi-asserted-by":"crossref","unstructured":"Quintarelli C, Sivori S, Caruso S. Efficacy of third-party chimeric antigen receptor modified peripheral blood natural killer cells for adoptive cell therapy of B-cell precursor acute lymphoblastic leukemia. Leukemia. 2020; 34(4):1102-1115.","DOI":"10.1038\/s41375-019-0613-7"},{"key":"61488","doi-asserted-by":"crossref","unstructured":"Ueda T, Kumagai A, Iriguchi S. Non-clinical efficacy, safety and stable clinical cell processing of induced pluripotent stem cell-derived anti-glypican-3 chimeric antigen receptor-expressing natural killer\/innate lymphoid cells. Cancer Sci. 2020; 111(5):1478-1490.","DOI":"10.1111\/cas.14374"},{"key":"61489","doi-asserted-by":"crossref","unstructured":"Tang SY, Zha S, Du Z. Targeted integration of EpCAM-specific CAR in human induced pluripotent stem cells and their differentiation into NK cells. Stem Cell Res Ther. 2021; 12(1):580.","DOI":"10.1186\/s13287-021-02648-4"},{"key":"61490","doi-asserted-by":"crossref","unstructured":"Li Y, Hermanson DL, Moriarity BS. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Cell Stem Cell. 2018; 23(2):181-192.e5.","DOI":"10.1016\/j.stem.2018.06.002"},{"key":"61491","doi-asserted-by":"crossref","unstructured":"He B, Mai Q, Pang Y. Cytokines induced memory-like NK cells engineered to express CD19 CAR exhibit enhanced responses against B cell malignancies. Front Immunol. 2023; 14:1130442.","DOI":"10.3389\/fimmu.2023.1130442"},{"key":"61492","doi-asserted-by":"crossref","unstructured":"Rotolo A, Caputo VS, Holubova M. Enhanced anti-lymphoma activity of CAR19-iNKT cells underpinned by dual CD19 and CD1d targeting. Cancer Cell. 2018; 34(4):596-610.e11.","DOI":"10.1016\/j.ccell.2018.08.017"},{"key":"61493","doi-asserted-by":"crossref","unstructured":"Simonetta F, Lohmeyer JK, Hirai T. Allogeneic CAR invariant natural killer T cells exert potent antitumor effects through host CD8 T-cell cross-priming. Clin Cancer Res. 2021; 27(21):6054-6064.","DOI":"10.1158\/1078-0432.CCR-21-1329"},{"key":"61494","doi-asserted-by":"crossref","unstructured":"Magnani CF, Gaipa G, Lussana F. Sleeping Beauty-engineered CAR T cells achieve antileukemic activity without severe toxicities. J Clin Invest. 2020; 130(11):6021-6033.","DOI":"10.1172\/JCI138473"},{"key":"61495","doi-asserted-by":"crossref","unstructured":"Rischer M, Pscherer S, Duwe S. Human gammadelta T cells as mediators of chimaeric-receptor redirected anti-tumour immunity. Br J Haematol. 2004; 126(4):583-592.","DOI":"10.1111\/j.1365-2141.2004.05077.x"},{"key":"61496","doi-asserted-by":"crossref","unstructured":"Deniger DC, Switzer K, Mi T. Bispecific T-cells expressing polyclonal repertoire of endogenous y\u00f6 T-cell receptors and introduced CD19-specific chimeric antigen receptor. Mol Ther. 2013; 21(3):638-647.","DOI":"10.1038\/mt.2012.267"},{"key":"61497","doi-asserted-by":"crossref","unstructured":"Polito VA, Cristantielli R, Weber G. Universal ready-to-use immunotherapeutic approach for the treatment of cancer: expanded and activated polyclonal \u03b3\u03b4 memory T cells. Front Immunol. 2019; 10:2717.","DOI":"10.3389\/fimmu.2019.02717"},{"key":"61498","doi-asserted-by":"crossref","unstructured":"Capsomidis A, Benthall G, Van Acker HH. Chimeric antigen receptor-engineered human gamma delta T cells: enhanced cytotoxicity with retention of cross presentation. Mol Ther. 2018; 26(2):354-365.","DOI":"10.1016\/j.ymthe.2017.12.001"},{"key":"61499","doi-asserted-by":"crossref","unstructured":"Rozenbaum M, Meir A, Aharony Y. Gamma-delta CAR-T cells show CAR-directed and independent activity against leukemia. Front Immunol. 2020; 11:1347.","DOI":"10.3389\/fimmu.2020.01347"},{"key":"61500","doi-asserted-by":"crossref","unstructured":"Wallet MA, Nishimura T, Del Casale C. Induced pluripotent stem cell-derived gamma delta CAR-T cells for cancer immunotherapy. Blood. 2021; 138(Suppl 1):2771.","DOI":"10.1182\/blood-2021-149095"}],"container-title":["Haematologica"],"original-title":[],"link":[{"URL":"https:\/\/haematologica.org\/article\/download\/haematol.2023.284604\/76990","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/haematologica.org\/article\/download\/haematol.2023.284604\/77043","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/haematologica.org\/article\/download\/11596\/76990","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T10:06:37Z","timestamp":1794045997000},"score":1,"resource":{"primary":{"URL":"https:\/\/haematologica.org\/article\/view\/haematol.2023.284604"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,10]]},"references-count":57,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2024,6,1]]}},"URL":"https:\/\/doi.org\/10.3324\/haematol.2023.284604","relation":{},"ISSN":["1592-8721","0390-6078"],"issn-type":[{"value":"1592-8721","type":"electronic"},{"value":"0390-6078","type":"print"}],"subject":[],"published":{"date-parts":[[2024,5,10]]}}}