Introduction: Immunotherapies targeting CD19, such as blinatumomab and CAR T cells, have shown remarkable efficacy in relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). However, many adults fail to respond to blinatumomab, and while CD19 CAR T cells induce high initial response rates, relapse occurs in up to 50% of patients. Patients (pts) who fail CD19-targeted immunotherapies have dismal outcomes with limited therapeutic options. Tumor escape through epitope loss represents a major challenge, especially as these therapies move into earlier treatment lines. To address the need for novel targeted therapies, we have developed CAR T cells against the B-cell activating factor receptor (BAFF-R), a B-cell marker functionally expressed in B-ALL, including CD19-negative relapses (Qin et al., Sci Transl Med. 2019). Given the essential role of BAFF-R in B-cell function and survival, the ability of malignant cells to evade therapy by antigen downregulation may be limited.

Methods: This is a phase 1 dose-escalation trial of BAFFR-CAR T cells (PMB-CT01) in pts with r/r B-ALL who are ineligible for, or who failed prior CD19-targeted therapy (NCT04690595). Dose escalation follows a modified 3+3 design with 4 dose levels (DL). DL-1 (de-escalation) and DL1 (starting dose) consist in infusion with 20M and 50M CAR T cells, respectively, after lymphodepletion (LD) with cyclophosphamide only. DL2, DL3, and DL4 consist in infusion with 50M, 200M, and 600M cells, respectively, after LD with cyclophosphamide and fludarabine.

Results: Accrual is ongoing with 6 pts enrolled (3 at DL1, and 3 at DL2). The median age is 36 (31-59) years, with 4/6 males. Pts received a median of 5 (2-5) prior lines of treatment; all 6 received prior blinatumomab, 4/6 patients received prior CD19 CAR T cells (including all 3 pts treated on DL2), and 4/6 patients had CD19-negative disease. All pts had pre-LD marrow disease >5% and/or extramedullary disease (EMD) involvement. The median % pre-LD marrow blasts for pts with marrow involvement was 35% (range: 30-40) and 3 pts had evidence of pre-LD EMD. No DLT has been observed so far. Tolerability has been excellent so far with no grade ≥3 cytokine release syndrome (CRS) and only 1 pt experienced grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS) that resolved without intervention. Four pts experienced CRS, all being grade 1 except for one with grade 2.

At DL1, 1 out of 3 pts responded and achieved undetectable minimal residual disease (MRD-) complete remission (CR) and then transitioned to allogeneic HCT. Another pt on DL1 had evidence of progressive disease in the cerebrospinal fluid (CSF) after a transient response on day 15 evaluation. At DL2, all 3 pts achieved MRD- CR or CR with complete count recovery (CRi), and 2 pts transitioned to transplant so far. Three out of 4 responders had CD19-negative disease and 2 of them had evidence of EMD pre-LD. Among the 3 responders who underwent transplant, the median time from CAR T cell infusion to transplant was 91 days (range: 88-177). At the time of data cut off and with a median follow up of 180 days (range: 39-655), all 4 responders remain in remission.

Robust CAR T cell expansion was observed in all 6 pts, with peak levels occurring between days 11 and 21 post-infusion (mean peak for DL1: 14.3% ± 6.7%; DL2: 21.4% ± 5.4% of the CD3+ population). CAR T cells persisted for up to 6 months as of the current data collection. Low levels of inflammatory cytokines, such as IL-6, were detected in the serum throughout the course. In the 3 patients who had CSF evaluation on day 28, BAFFR-CAR T cells were detected at 1.98%, 8.9%, and 37.9%, respectively.Conclusion: BAFFR-CAR T cell therapy demonstrated an excellent initial safety profile. Following LD with cyclophosphamide and fludarabine, the 50M dose demonstrated robust expansion and promising activity in heavily pretreated pts with r/r B-ALL who had failed prior CD19-targeted therapies and had limited treatment options. Treatment successfully transitioned pts to potentially curative transplant.

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2025
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