Favorable Safety Profile and Durable Responses to Pmb-CT01 (BAFFR-CAR T Cell) Therapy in Patients with B-Cell Lymphomas Ineligible for or Who Failed CD19-Targeted Therapy, Including CD19-Negative Disease
Authors: Del Real Marissa Morales , Baird John H. , Chen Lu , Song Joo Y. , Wang Xiuli , Kambhampati Swetha , Macias Alan , Marcucci Emanuela C , Cha Soungchul , Dong Zhenyuan , Kim Teresa , Barva Baishakhi , Puverel Sandrine , Liu-Michael Qing , Cheng Hazel Ting-Ying , Forman Stephen J. , Kwak Larry W. , Budde Lihua E. 
Published: December 2024

Introduction: CD19-directed therapies have transformed the care of patients with B-cell malignancies, but many patients still relapse or have refractory disease. Relapse with CD19 loss as a mechanism of tumor escape is common and poses a significant challenge, particularly as these treatments move into earlier lines of therapy. Patients who are ineligible for or have failed prior CD19-targeted therapy have limited salvage options and a very poor prognosis, highlighting the urgent need to develop alternative approaches to improve the outcomes. We have developed CAR T cells against a new target, the B-cell activating factor receptor (BAFF-R). BAFF-R is a marker of B cells that is also functionally expressed in non-Hodgkin lymphomas (NHL), including in patients with CD19-negative relapse (Qin et al., Sci Transl Med. 2019). Since BAFF-R is a critical regulator of B-cell function and survival, the capacity of B-cell malignancies to evade therapy by downregulation of BAFF-R expression may also be limited.
Methods: We are conducting a phase 1 clinical trial of BAFFR-CAR T cells in patients with relapsed/refractory (r/r) NHL (NCT05370430). Primary endpoints are dose limiting toxicities (DLTs) and all other toxicities. Secondary endpoints include response rate, minimal residual disease (MRD) negative rate, PFS and OS. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are graded according to ASTCT consensus criteria. Response is evaluated using the Lugano 2014 criteria.
Results: Six patients have received BAFFR-CAR T cell infusion. Four patients had stage IV mantle cell lymphoma (MCL), one patient had stage III T cell/histiocyte rich large B-cell lymphoma (THRBCL), and one patient had stage II marginal zone lymphoma (MZL). Median age was 67.5 years (range: 41-75) and median number of prior lines of therapy was 3.5 (range: 1-10). Half of the patients had received prior CD19 CAR T cells, and two patients had received a CD3/CD20 bispecific antibody. The THRBCL patient was negative for both CD19 and CD20 expression. Three patients were treated at dose level 1 (DL1; 50M BAFFR-CAR T cells), and three were treated at dose level 2 (DL2; 200M CAR T cells). There were no DLTs. All five evaluable patients experienced grade 1 CRS, and two patients had grade 1 ICANS. The first five patients all achieved a best response of complete response (CR), with ongoing responses ranging from 4 to 20 months (13-20 months at DL1). Response assessment for the last patient is pending. Results for additional patients who are undergoing treatment will be available for presentation at the meeting.
Clinical responses correlated with robust BAFFR-CAR T cell expansion, with a peak in CAR T cell levels observed at a median of 12 days post-CAR T cell infusion (range 11-14; n=3) at DL1 and 12.5 days (range 12-13; n=2) at DL2, as measured by WPRE qPCR. Peak levels in patients treated at DL2 (median 4.43M copies/mL blood; range 3.2M-5.6M; n=2) were not higher than in DL1 patients (median 5.6M copies/mL blood; range 2.1M-8.9M; n=3). Sixty percent of patients (3/5) showed CAR T cell persistence at 3 months post-infusion. CAR-positive cells analyzed by flow cytometry showed low to no expression of exhaustion markers PD1, Lag3 and Tim3. The polyfunctionality of BAFFR-CAR T cell products from the DL1 cohort (n=3) was assessed using the Isoplexis single-cell analysis platform. All three products released a combination of functional effector, stimulatory, chemoattractive, regulatory and inflammatory cytokines upon antigen stimulation. Notably, the CAR T cell product with the highest polyfunctional index in antigen-stimulated CD4+ and CD8+ cells was the only product still detectable at 6 months post-infusion. Additional correlative studies, including serial T cell phenotyping and clonality in peripheral blood after treatment are ongoing.
Conclusions: With a 100% CR rate, including durable responses at dose level 1 and a favorable initial safety profile, BAFFR-CAR T cells constitute a promising therapeutic option for patients with r/r B-cell malignancies who are ineligible for or have failed prior CD20- or CD19-targeted therapy, including with CD20 or CD19 antigen loss. The correlation of clinical responses with robust CAR T cell expansion and persistence, as well as polyfunctionality and low exhaustion marker expression, underscores the potential of BAFFR-CAR T cells in providing long-lasting remissions.