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However, a common limitation is the high frequency of antigen loss, which leads to r\/r B-ALL progression. To overcome progression caused by antigen loss, bi-specific CAR-T immunotherapies targeting both CD19 and CD22 may offer enhanced efficacy in eliminating r\/r B-ALL and preventing relapse by hindering leukemia cell proliferation. In this study, we present both pre-clinical and clinical findings from an ongoing trial (NCT04303520) assessing the therapeutic efficacy of the CD19-CD22 bi-specific CAR-T therapy for r\/r B-ALL patients. Pre-clinical data from animal models reveal that CD19-CD22 CAR-T cells effectively induce cytotoxicity, thus suppressing B-ALL cell proliferation. Notably, this dual-targeted approach outperforms single-target CAR-T treatments. From the Phase I trial encompassing 35 participants, 37.1% (13 out of 35 patients) experienced cytokine release syndrome, with only a single case of Grade\u00a0III \u00a0 severity. Importantly, no neurotoxicity episodes were recorded post CD19-CD22 CAR-T administration. Common adverse events included hematological, gastrointestinal, and nutrition-related disturbances. B-ALL patients undergoing stem cell transplantation in tandem with CAR-T therapy exhibited a pronounced improvement in overall survival compared to those treated solely with CAR-T. The median overall survival duration was 21.49\u2009\u00b1\u20094.4\u00a0months (95% CI: 14.31\u201331.40\u00a0months), meanwhile one-year PFS and OS are 0.37 (95% CI, 0.21\u20130.49) and 0.62 (95% CI: 0.52\u20130.71), respectively. Clinical monitoring did not identify significant side effects associated with the CD19-CD22 regimen. To monitor the inflammation-associated factors accompanying CAR-T therapy, the peak value of CAR DNA copies was reached around Day 10, accompanied by a similar trend in the levels of inflammatory factors, including IFN-\n                    <jats:italic>\u03b3<\/jats:italic>\n                    , Granzyme B, IL-6, and CRP. Collectively, our data advocate for the potential role of bi-specific CD19-CD22 CAR-T therapy in addressing r\/r B-ALL.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:italic>Trial registration number<\/jats:italic>\n                    ClinicalTrials.gov (No. NCT04303520).\n                  <\/jats:p>","DOI":"10.1007\/s10238-025-01637-8","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T05:11:50Z","timestamp":1753679510000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A bi-specific CAR-T cell therapy targeting CD19 and CD22 in relapsed or refractory B-ALL"],"prefix":"10.1007","volume":"25","clinical-trial-number":[{"clinical-trial-number":"nct04303520","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Qiuling","family":"Ma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runhong","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingming","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songfu","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Min","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shufang","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohong","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haigang","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuedong","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingxing","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,28]]},"reference":[{"issue":"9","key":"1637_CR1","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1001\/jama.2021.0669FromNLM","volume":"325","author":"PA Brown","year":"2021","unstructured":"Brown PA, Ji L, Xu X, Devidas M, Hogan LE, Borowitz MJ, Raetz EA, Zugmaier G, Sharon E, Bernhardt MB, et al. Effect of postreinduction therapy consolidation with blinatumomab vs chemotherapy on disease-free survival in children, Adolescents, and young adults with first relapse of B-cell acute lymphoblastic leukemia: a randomized clinical trial. JAMA. 2021;325(9):833\u201342. https:\/\/doi.org\/10.1001\/jama.2021.0669FromNLM.","journal-title":"JAMA"},{"issue":"9757","key":"1637_CR2","doi-asserted-by":"publisher","first-page":"2009","DOI":"10.1016\/s0140-6736(10)62002-8FromNLM","volume":"376","author":"C Parker","year":"2010","unstructured":"Parker C, Waters R, Leighton C, Hancock J, Sutton R, Moorman AV, Ancliff P, Morgan M, Masurekar A, Goulden N, et al. Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial. 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