BAFFR-CAR T cells (PMB-CT01) demonstrate durable responses and manageable toxicities in relapsed/refractory B-cell lymphomas with prior CD19-directed therapy failure or CD19-negative disease

Abstract Introduction: CD19-directed CAR T cell therapies have redefined treatment paradigms for B-cell malignancies. However, relapse is common and often associated with loss of CD19 expression. Patients who relapse after or are ineligible for CD19-targeted therapies face limited treatment options and poor outcomes. We have developed CAR T cells against the B-cell activating factor receptor (BAFF-R), a functionally important receptor expressed on both normal and malignant B cells. Unlike CD19 and CD20, BAFF-R plays a critical role in B-cell function and survival, making therapeutic escape via antigen downregulation less likely. Importantly, BAFF-R is expressed in CD19-negative relapse samples, supporting its relevance in settings where CD19-targeted therapies fail (Qin et al., Sci Transl Med. 2019). PMB-CT01 is a novel autologous CAR T cell therapy currently under evaluation in a first-in-human phase 1 study in patients with B-cell lymphomas. Methods: We are conducting a dose-escalation phase 1 trial (NCT05370430) of PMB-CT01 in patients with relapsed/refractory (r/r) B-cell non-Hodgkin lymphomas (B-NHL). The trial has been expanded to a multicenter study. Patients were treated at either dose level 1 (DL1; 50×106 CAR T cells) or dose level 2 (DL2; 200×106 CAR T cells). The primary objective is to evaluate safety, including dose-limiting toxicities (DLTs); secondary endpoints include overall response rate (ORR), complete response (CR) rate, minimal residual disease (MRD) negativity, progression-free survival (PFS), and overall survival (OS). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are assessed per ASTCT consensus criteria. Disease response is evaluated using the Lugano 2014 criteria. Results: Seven patients have been treated so far. Diagnoses included mantle cell lymphoma (MCL; n=4), CD19- and CD20-negative T cell/histiocyte-rich large B-cell lymphoma (THRBCL; n=1), marginal zone lymphoma (MZL; n=1) and follicular lymphoma (FL; n=1). Median age was 62 years (range: 41-75), with 6/7 male patients. Patients had received 1-10 prior lines of treatment, including CD19 CAR T cells (n=4) and a CD3/CD20 bispecific antibody (n=2). Three patients were treated at DL1 and four at DL2. No DLTs occurred. All seven patients experienced only grade 1 CRS; two had grade 1 ICANS that resolved without corticosteroids. No grade ≥2 CRS or ICANS events were reported. All patients achieved CR at 1 or 3 months post-infusion (100% CR rate). Responses have been durable, with no relapses and ongoing remissions extending up to 32 months (median 17 months; range 3-32 months). Among MCL patients, 3/3 tested were MRD-negative by both high-resolution flow cytometry and next-generation sequencing (NGS) at 1 and ≥6 months post-treatment. Robust CAR T cell expansion was observed in all patients tested. Given the favorable safety profile and durable remissions observed thus far, 200x106 BAFFR-CAR T cells is expected to be the recommended dose for future studies. We anticipate that results from the completed nine-patient dose-escalation portion of the trial will be available for presentation at the meeting. Upon identification of the recommended phase 2 dose (RP2D), three histology expansion cohorts will open in parallel: 1) FL; 2) MCL; and 3) Large B-cell lymphoma (LBCL) to further assess safety and efficacy in each subtype.Conclusions: PMB-CT01 demonstrated an exceptionally favorable safety profile and 100% CR rate in r/r B-NHL patients with poor-prognosis features, including CD19-negative disease and prior CD19 CAR T cell therapy. The durability of response at both dose levels supports the potential of BAFFR-CAR T cells as a promising therapeutic option in patients who are not candidates for or have relapsed after CD19-directed therapy. Continued enrollment and follow-up are ongoing, and updated clinical and correlative data will be presented at the meeting.