FDA Grants RMAT and Fast Track Designations to Allogeneic CAR T-Cell Therapy for B-NHL

The FDA granted CB-010, an allogeneic chimeric antigen receptor (CAR) T-cell therapy regenerative medicine advanced therapy (RMAT) designation for patients with relapsed or refractory large B cell lymphoma (LBCL) and fast track designation for patients with relapsed or refractory B cell non-Hodgkin lymphoma (R/R B-NHL), according to a press release from Caribou Biosciences, Inc.¹

CB-010, an allogeneic anti-CD19 CAR-T cell therapy, is being evaluated in the ongoing ANTLER phase 1 clinical trial (NCT04637763) in patients with R/R B-NHL. The FDA designations are based on the outcomes of 6 patients evaluated at dose level 1 who all had a complete response (CR), with 3 out of 6 patients maintaining a durable complete response at 6 months.

“We are encouraged that CB-010 has demonstrated early potential as an off-the-shelf cell therapy that may meaningfully rival autologous cell therapies,” Rachel Haurwitz, PhD, Caribou’s president and chief executive officer, said in a statement.

CB-010 is an allogeneic CAR-T cell therapy targeting CD19 which was created with the Cas9 CRISPR hybrid RNA-DNA guide technology meant to avoid off-target gene editing. Using CRISPR, a CD19-specific CAR was inserted into the TRAC gene for this agent. It is the first allogeneic anti-CD19 CAR T-cell therapy in clinical trials to include a PD-1 knockout, which is aimed to improve the persistence of antitumor activity by preventing premature exhaustion of CAR T cells due to PD-L1 interaction.

The phase 1 ANTLER trial enrolled patients with aggressive B-NHL who had received at least 2 prior lines of chemoimmunotherapy and had not received prior CD19-targeted therapy.² Part A of the trial is a 3+3 dose escalation design. The first 6 patients received lymphodepletion with cyclophosphamide plus fludarabine, followed by a single dose of 40 × 10⁶ CAR T cells at dose level 1. The cohort of patients at the second dose level of 80 × 10⁶ viable CAR T cells has not completed enrollment. The objective of part A is to determine the safety, maximum tolerated dose, and recommended phase 2 dose. This will be followed by a dose expansion part which will investigate tumor response.

All 6 patients had a best response of CR, but 1 patient with diffuse LBCL progressed after 3 months, and 1 each with follicular lymphoma and mantle cell lymphoma had progressed after 6 months. Three others continued on study treatment, with 1 patient with follicular lymphoma demonstrating a durable CR at over 15 months.^1,2

CB-010 had encouraging safety data based on these 6 patients.² No graft-vs-host disease was reported. The most common treatment-emergent adverse events (AEs) were decreased neutrophils in 5 patients, decreased platelets in 4 patients, and anemia in 4 patients. Treatment-related AEs of grade 3 or higher included 3 cases of decreased platelets, 3 cases of decreased white blood cells, 1 with decreased neutrophils, 1 with decreased leukocytes, 1 with increased lactate dehydrogenase, and 1 instance of grade 3 immune effector cell–associated neurotoxicity syndrome.

The RMAT and fast track designations will help expedite the development and regulatory review processes for CB-010 based on the unmet need that this agent is meant to provide. They will make the investigational agent eligible for Priority and Rolling Reviews, and 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,” said Haurwitz.¹

_References

_{1. Caribou Biosciences announces the FDA granted regenerative medicine advanced therapy (RMAT) and Fast Track designations to CB-010, an allogeneic anti-CD19 CAR-T cell therapy. Caribou Biosciences. November 29, 2022. Accessed November 30, 2022. https://bit.ly/3FhH6Qg}

_{2. Nastoupil LJ, O’Brien S, Holmes HE, et al. First-in-human trial of CB-010, a CRISPR-edited allogeneic anti-CD19 CAR-T cell therapy with a PD-1 knock out, in patients with relapsed or refractory B cell non-Hodgkin lymphoma (ANTLER Study). Presented at: European Hematology Association (EHA) 2022 Hybrid Congress; Vienna, Austria; June 10, 2022. Accessed November 30, 2022. https://bit.ly/3XP9391}