The FDA has granted Caribou Biosciences' CB-010 both regenerative medicine advanced therapy (RMAT) designation and fast track designation for treating patients with relapsed or refractory B-cell non-Hodgkin lymphoma (R/R B-NHL). The regulatory recognitions are based on compelling early efficacy data from the ongoing phase 1 ANTLER trial, where all six patients evaluated at the first dose level achieved complete responses.
Breakthrough Clinical Results Drive Regulatory Recognition
CB-010, an allogeneic anti-CD19 CAR-T cell therapy, demonstrated remarkable efficacy in the initial cohort of the ANTLER phase 1 clinical trial (NCT04637763). All six patients achieved a best response of complete response (CR), with three out of six patients maintaining durable complete responses at six months. One patient with follicular lymphoma has demonstrated a durable CR lasting over 15 months and continues on study treatment.
"We are encouraged that CB-010 has demonstrated early potential as an off-the-shelf cell therapy that may meaningfully rival autologous cell therapies," said Rachel Haurwitz, PhD, Caribou's president and chief executive officer.
Novel CRISPR-Engineered Design Features
CB-010 distinguishes itself as the first allogeneic anti-CD19 CAR-T cell therapy in clinical trials to include a PD-1 knockout. This innovative design aims to improve the persistence of antitumor activity by preventing premature exhaustion of CAR-T cells due to PD-L1 interaction. The therapy was created using Caribou's Cas9 CRISPR hybrid RNA-DNA guide technology, specifically designed to avoid off-target gene editing. Using CRISPR, a CD19-specific CAR was inserted into the TRAC gene.
Trial Design and Patient Population
The phase 1 ANTLER trial enrolled patients with aggressive B-NHL who had received at least two prior lines of chemoimmunotherapy and had not received prior CD19-targeted therapy. Part A follows a 3+3 dose escalation design, with the first six patients receiving lymphodepletion with cyclophosphamide plus fludarabine, followed by a single dose of 40 × 10⁶ CAR-T cells at dose level 1. The second dose level of 80 × 10⁶ viable CAR-T cells has not completed enrollment.
Encouraging Safety Profile
CB-010 demonstrated encouraging safety data in the initial six patients, with no graft-versus-host disease reported. The most common treatment-emergent adverse events were decreased neutrophils in five patients, decreased platelets in four patients, and anemia in four patients. Treatment-related adverse events of grade 3 or higher included three cases each of decreased platelets and decreased white blood cells, along with single instances of decreased neutrophils, decreased leukocytes, increased lactate dehydrogenase, and grade 3 immune effector cell-associated neurotoxicity syndrome.
Regulatory Pathway Advantages
The RMAT and fast track designations will expedite CB-010's development and regulatory review processes, making the investigational agent eligible for Priority and Rolling Reviews, and potentially Accelerated Approval if it meets relevant criteria. "RMAT and Fast Track designations for CB-010 are important recognitions of the significant unmet patient need for an off-the-shelf cell therapy in the treatment of aggressive B-NHL," Haurwitz stated.
Clinical Outcomes and Disease Progression
While all six patients initially achieved complete responses, some experienced disease progression over time. One patient with diffuse large B-cell lymphoma progressed after three months, and one each with follicular lymphoma and mantle cell lymphoma progressed after six months. However, three patients continued on study treatment, demonstrating the potential for durable responses in this patient population.
