Background: Dual-targeted CAR-T cell therapies may help overcome mechanisms of resistance associated with antigen escape. We evaluated an investigational, autologous CD19/CD22-targeted second-generation CAR construct incorporating a 4-1BB costimulatory domain and fully human scFv domains. Here, we report outcomes in adult patients with relapsed/refractory (R/R) B-cell malignancies.

Methods: Nine adult patients with R/R B-cell malignancies received an investigational CD19/CD22-targeted CAR-T cell product since January 2020. Treatment was performed based on recommendations of the interdisciplinary Cell Therapy Board at the University Hospital Tübingen, and after extensive counseling with the patient´s informed consent based on hospital exemption for advanced therapy medicinal products (ATMP) treatment. For CD19/CD22 CAR-T cell production lymphocytes were transduced with a lentiviral vector encoding a human anti-CD19 scFv M19217-1 and human anti-CD22 scFv 16p17 (kindly provided by Miltenyi Biotec) and cells amplified in the Miltenyi Prodigy systems in our academic GMP facility at the University Hospital. Lymphodepletion was performed using fludarabine (25 mg/m²/day, days –5 to –3) and cyclophosphamide (1000 mg/m², day –3). Seven patients received autologous T-cells; two received donor-derived T-cells from prior allogeneic stem cell transplant donors in a dose of 3x10E6 CD19/CD22 CAR-T cells/kg bodyweight.

Results: Diagnoses included B-cell acute lymphoblastic leukemia (B-ALL, n=3), mantle cell lymphoma (MCL, n=1), Richter transformation–DLBCL (n=2), primary mediastinal B-cell lymphoma (PMBCL, n=1), post-transplant lymphoproliferative disorder (PTLD, n=1), and diffuse large B-cell lymphoma (DLBCL, n=1). Best responses included complete remission (CR) in 6 patients (66%) and progressive disease (PD) in 3 (33%). All B-ALL patients achieved CR; among aggressive B-cell lymphomas, CR was achieved in 3 of 6 patients (50%).

According to Kaplan-Meier estimates, the median follow-up was 25.7 months (range 0.8–60.4 months) with a median progression-free survival (PFS) of 13.6 months (29.8 months in B-ALL; 7.5 months in lymphoma). The median overall survival (OS) was 60.4 months, (60.4 months in B-ALL; 13.8 months in lymphoma).

CAR-T cell persistence was assessed throughout the follow-up period. In two ALL cases, repeated CAR-T cell infusions induced renewed complete remission (CR) after relapse associated with loss of CAR-T cell persistence: one following MRD relapse, and one following relapse with cerebral leukemic infiltration.

Safety: Grade 4 neutropenia occurred in 8 patients (89%), with a median duration of 10 days. Cytokine release syndrome (CRS) was observed in 7 patients (77%), including Grade 3–4 CRS in 2 patients (22%), with a median onset at day 1 and duration of 3 days. Immune effector cell–associated neurotoxicity syndrome (ICANS) occurred in 2 patients (22%), including one Grade 3–4 event. Reported complications included one case each of immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), Candida sepsis, Grade III intestinal GvHD, and squamous cell carcinoma. The main causes of death were infection (n=1) and progressive disease (n=2).

Conclusion: The investigational CD19/CD22-targeted CAR-T cell product demonstrated encouraging efficacy with a manageable safety profile in heavily pretreated adult patients with relapsed/refractory B-cell malignancies, including post-transplant settings. Dual targeting may offer therapeutic advantages in overcoming antigen escape and achieving durable remissions. Based on promising results, a Phase I dose-finding and efficacy study of a third-generation CAR-T cell product (MB-CART19.22), is planned in adult and pediatric patients with relapsed or refractory B-cell malignancies.

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2025
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