PD-L1-armored CAR-T followed by allo-HSCT yields 7-year remission in refractory B-cell ALL

BackgroundAntigen escape and PD-L1/PD-1 axis-mediated immunosuppression in the tumor microenvironment (TME) are the predominant drivers of treatment failure in adult patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). CD19-targeted CAR-T monotherapy has limited ability to overcome these two core resistance mechanisms, and achieving long-term durable remission remains a critical unmet clinical need in adults with high-risk, chemorefractory B-ALL.MethodsThis is a single-center, retrospective case report of an adult patient with early-relapsed, chemorefractory B-ALL. Two independent CAR-T products were manufactured from the patient’s autologous peripheral blood mononuclear cells (PBMCs): (1) CD19 CAR-T cells containing an anti-CD19 single-chain variable fragment (scFv), a CD28 transmembrane domain, a 4-1BB co-stimulatory domain, and a CD3ζ signaling domain; (2) PD-L1-armored CD22 CAR-T cells containing an anti-CD22 scFv, a CD8 transmembrane domain, a 4-1BB co-stimulatory domain, a CD3ζ signaling domain, and a membrane-tethered anti-PD-L1 scFv for spatially restricted immune checkpoint modulation. The two CAR-T products were co-infused at doses of 5.0×105 cells/kg (CD19 CAR-T) and 3.1×105 cells/kg (PD-L1-armored CD22 CAR-T), respectively. We evaluated the feasibility, anti-leukemic efficacy, and long-term safety profile of this regimen as a bridging strategy to allogeneic hematopoietic stem cell transplantation (allo-HSCT). This treatment was administered under an institutional compassionate use program approved by the Ethics Committee of the Second Hospital of Hebei Medical University (approval number: 2017-R207), with written informed consent obtained from the patient prior to all treatment procedures. Comprehensive diagnostic workup for B-ALL was performed using 8-color multiparameter flow cytometry (MFC), conventional G-banding cytogenetic analysis, and multiplex leukemia fusion gene screening. Serial lumbar punctures with triple intrathecal chemotherapy (dexamethasone 5 mg + methotrexate 10 mg + cytarabine 30 mg) were performed throughout the treatment course; no abnormalities were detected in cerebrospinal fluid (CSF) routine, biochemistry, or flow cytometry assays, and no evidence of central nervous system (CNS) leukemia involvement was observed at any time point. This study is a retrospective observational analysis of a single clinical case, not a prospective interventional clinical trial, and thus was exempt from clinical trial registration requirements in accordance with institutional and national regulatory guidelines for retrospective observational studies.ResultsThe patient achieved minimal residual disease (MRD)-negative complete remission (CR) on day 14 post-infusion, as confirmed by 8-color MFC (detection sensitivity: 0.01%) and next-generation sequencing (NGS) of immunoglobulin heavy chain (IGH) gene rearrangements (limit of detection [LOD]: 10−6). Peak in vivo expansion of CAR-T cells was observed on day 10 post-infusion, with CD19 CAR-T cells accounting for 43.25% and CD22 CAR-T cells accounting for 14.58% of circulating CD3+ T lymphocytes. Only grade 1 cytokine release syndrome (CRS), per the American Society for Transplantation and Cellular Therapy (ASTCT) consensus criteria, occurred and resolved completely with supportive care; no immune effector cell-associated neurotoxicity syndrome (ICANS) was observed. Following consolidative allo-HSCT, rapid hematopoietic reconstitution was achieved, with neutrophil engraftment on day +12 and platelet engraftment on day +14, consistent with the median engraftment timeline for haploidentical HSCT at our institution. Complete donor chimerism (99.86%) was confirmed by short tandem repeat (STR) analysis on day +30 post-transplantation. Notably, the patient maintained MRD-negative sustained remission for 7 consecutive years, with no occurrence of acute or chronic graft-versus-host disease (GVHD) or late treatment-related adverse events. Complete immune reconstitution was achieved by 24 months post-transplantation, with sustained functional immune recovery and a Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) total score of 158/172 at the 7-year follow-up.ConclusionsThis case report details the clinical course of an adult patient with early-relapsed, chemorefractory B-ALL who achieved 7-year MRD-negative sustained remission after treatment with PD-L1-armored CD19/CD22 dual-targeted CAR-T cell co-infusion followed by consolidative allo-HSCT. Our preliminary clinical observation demonstrates that this integrated regimen may mitigate antigen escape and immunosuppressive TME-mediated drug resistance, and effectively function as a bridging strategy to allo-HSCT in high-risk patient populations. The 7-year event-free survival (EFS) and sustained disease control observed in this case provide valuable clinical insights for the structural optimization of armored CAR-T constructs and the design of future prospective clinical trials for R/R B-ALL.