BEAM-201 for the Treatment of Relapsed and/or Refractory (R/R) T-Cell Acute Lymphoblastic Leukemia (T-ALL) or T-Cell Lymphoblastic Lymphoma (T-LL): Initial Data from the Phase (Ph) 1/2 Dose-Exploration, Dose-Expansion, Safety, and Efficacy Study of Multiplex Base-Edited Allogeneic Anti-CD7 CAR-T-Cells
Authors: Diorio Caroline , Shaughnessy Paul , Farhadfar Nosha , Advani Anjali S. , Weng Wen-Kai , Youssoufian Hagop , Chen Guo , Nguyen Brown Felicia , Habtermariam Bahru , Kumar Lalit , Patel Jigar , Liu Shangbin (Gary) , Goyal Sunita , Simon Amy , Minella Alex C. , Teachey David T. 
Published: December 2024

Patients (Ps) with R/R T-ALL/T-LL have poor outcomes and limited therapeutic options. Hematopoietic stem cell transplantation (HSCT) is potentially curative; however, it requires minimal residual disease (MRD), which is difficult to attain as these Ps tend to be treatment refractory. In contrast to B-cell ALL, development of CAR-T-cell therapies for R/R T-ALL/T-LL is challenging due to shared antigen expression between healthy and malignant T-cells and the severity of disease while Ps wait for therapy. Allogeneic CAR-T-cell strategies may thus be particularly useful in the setting of R/R T-ALL/T-LL. However, allogeneic CAR-T-cells can lead to graft-vs-host disease (GvHD).

BEAM-201 is an investigational allogeneic, multiplex base-edited anti-CD7 CAR-T-cell therapy designed to address these limitations by simultaneously introducing 4 distinct single base mutations into TRAC, CD7, CD52, and PDCD1 genes to abolish functional proteins. This approach enables universal compatibility and reduces risk of GvHD, host rejection, fratricide, and tumor-expressed PDL-1-mediated immunosuppression. Alemtuzumab (Alz), a CD52-targeting monoclonal antibody, has been used with allogeneic CAR-T-cells to facilitate robust expansion and persistence. We report initial data from an ongoing Ph 1/2 dose-exploration (DE) and -expansion study (NCT05885464) evaluating the safety and efficacy of BEAM-201.

Primary objectives of Ph 1 were to determine the safety, tolerability, and recommended Ph 2 dose. BEAM-201 DE was performed across 4 dose levels (DLs; DL-1 60×106 cells; DL1 180×106 cells; DL2 360×106 cells; DL3 500×106 cells) in 2 parallel cohorts using either a fludarabine (30 mg/m2 ×4 days)/cyclophosphamide (500 mg/m2 ×3 days) (Flu/Cy) or Flu/Cy + Alz (20 mg ×1 day) lymphodepletion regimen at the investigator's discretion. Eligible Ps were aged 18-≤50 years with T-ALL/T-LL (CD7-positive ≥20% +blasts, with ≥2 relapses, first relapse post-transplant, or chemotherapy-refractory). After lymphodepletion, Ps received a single dose of BEAM-201 on Day 1. At Day 28 post-treatment, a response assessment was performed and appropriateness for HSCT was determined by the investigator. DE started at 180×106 cells, and for subsequent dose levels escalation and de-escalation were guided by available safety, efficacy, pharmacokinetic (PK)/pharmacodynamic data, using Bayesian optimal interval design. Depth of response analysis was based on MRD.

At data cutoff (June 11, 2024), 3 Ps had received BEAM-201 with follow up of either ≥28 days or early termination. P demographics: P1 (age 18, male, R/R bulky T-LL), P2 (29, male, post-transplant relapsed T-ALL), P3 (47, male, R/R bulky T-LL). P1 and P2 received Flu/Cy + Alz and BEAM-201 DLs at 180×106 and 60×106 viable CAR+ cells, respectively. P3 received Flu/Cy and BEAM-201 DL 180×106 cells.

P1 experienced 9 Grade (G) ≥3 treatment-emergent adverse events (TEAEs) (possibly related: G3 pneumonia, G3 lung infection, G3 febrile neutropenia, G4 cytokine release syndrome [CRS], G3 nausea) and 5 serious AEs (SAEs) (possibly related: G4 CRS, G3 lung infection, G3 febrile neutropenia). P2 experienced 6 G ≥3 TEAEs (possibly related: G4 lymphocyte, WBC and platelet count decrease, G3 febrile neutropenia) and no SAEs. P3 experienced no G ≥3 TEAEs or SAEs. All Ps experienced CRS (P1/2/3: max G 4/1/1) and no Ps developed immune effector cell-associated neurotoxicity syndrome or GvHD. One death (P1) occurred 40 days post-infusion due to disease progression and was deemed unrelated to study treatment or procedure.

PK analysis in P1 and P2 showed CAR-T expansion and persistence up to 28 days; P3 pending. Day 28 clinical response assessment of bone marrow (BM) aspirate and biopsy samples was not carried out for P1 due to disease progression after initial transient response. P2 showed complete response with incomplete (CRi) hematologic recovery and P3 had complete response (CR). MRD-negative (&lt;0.01%) response was achieved in P2, while P3 had absence of BM involvement pre- and post-treatment. P2 and P3 were deemed suitable for HSCT based on response.

These initial data show a BEAM-201 safety profile consistent with underlying disease, lymphodepletion, and AEs associated with CAR-T therapy. PK and safety data support continued Ph 1 dose exploration. Early evidence of efficacy with CAR-T-cell doses &lt;200 million, as measured by CRi/CR in 2/3 Ps, is very encouraging. Updated data will be presented.