The U.S. Food and Drug Administration (FDA) has granted Regenerative Medicine Advanced Therapy (RMAT) designation to LYL314, a next-generation dual-targeting CD19/CD20 CAR T-cell therapy developed by Lyell Immunopharma, Inc. (Nasdaq: LYEL) for the treatment of adult patients with relapsed and/or refractory large B-cell lymphoma (LBCL) after two or more prior lines of therapy.
The RMAT designation, which provides benefits similar to Fast Track and Breakthrough Therapy designations, was based on promising clinical data from Lyell's ongoing Phase 1/2 trial. This regulatory milestone follows the previous Fast Track designation for LYL314 in the same indication, further accelerating the development pathway for this innovative cell therapy.
"The RMAT designation for LYL314 highlights the transformative potential of this next-generation CAR T-cell therapy to address the unmet needs of patients with aggressive large B-cell lymphoma," said Lynn Seely, M.D., president and chief executive officer of Lyell. "We believe that by targeting both CD19 and CD20 with equal potency and manufacturing with a process that enriches for more naïve and central memory CAR T cells, LYL314 has the potential to offer patients with aggressive B-cell lymphoma more complete responses and longer duration of response than first-generation CAR T-cell therapies that only target CD19."
Promising Clinical Data
Initial data from the Phase 1/2 trial of LYL314 were presented at the American Society for Hematology 2024 Annual Meeting in December 2024. Among 17 efficacy-evaluable patients with relapsed or refractory LBCL in the third-line or later setting:
- Overall response rate was 94% (16/17 patients)
- Complete response rate was 71% (12/17 patients) by three months
- 71% of patients maintained responses at last follow-up (median follow-up of 6.3 months)
The safety profile appears favorable compared to existing CAR T therapies. In the safety-evaluable population of 23 patients:
- No Grade 3 or greater cytokine release syndrome (CRS) was reported
- Grade 3 immune effector cell-associated neurotoxicity syndrome (ICANS) was reported in 13% (3/23) of patients
- Median time to ICANS resolution was 5 days, with rapid improvement to Grade 2 or lower with standard therapy
Innovative Dual-Targeting Mechanism
LYL314 represents a significant advancement in CAR T-cell therapy design. Unlike first-generation CAR T therapies that target only CD19, LYL314 is designed as a true CD19/CD20 "OR" logic-gated CAR, targeting either CD19 or CD20 with full potency. This dual-targeting approach may help overcome antigen escape, a common mechanism of resistance to single-target CAR T therapies.
Additionally, the manufacturing process for LYL314 enriches for CD62L+ cells, generating more naïve and central memory CAR T cells with enhanced stemlike features and antitumor activity. These properties are designed to improve persistence and efficacy of the therapy.
Development Timeline and Regulatory Significance
Lyell has outlined an ambitious development plan for LYL314:
- Mid-2025: Present more mature data from patients in the third-line or later setting and initial data from second-line patients
- Late 2025: Present more mature data from second-line patients
- Mid-2025: Initiate pivotal program for third-line or later LBCL
- Early 2026: Initiate pivotal program for second-line LBCL
The RMAT designation, established under the 21st Century Cures Act, is intended to expedite development and review of regenerative medicine therapies for serious or life-threatening conditions. This designation provides Lyell with increased opportunities for FDA interaction, including early discussions about potential surrogate endpoints and the possibility of accelerated approval pathways.
Unmet Need in LBCL
Large B-cell lymphoma is the most common type of non-Hodgkin lymphoma, with approximately 18,000 patients diagnosed annually in the United States. Despite advances in first-line therapy, many patients experience relapse or refractory disease.
While current CD19-directed CAR T-cell therapies have shown efficacy in relapsed/refractory LBCL, challenges remain, including incomplete response rates, limited durability of response, and treatment-related toxicities. LYL314's dual-targeting approach and enhanced manufacturing process aim to address these limitations.
About Lyell Immunopharma
Lyell Immunopharma is a clinical-stage biotechnology company focused on developing next-generation CAR T-cell therapies for patients with hematologic malignancies and solid tumors. The company's technology platform aims to enhance CAR T-cell function through multiple mechanisms, including improving persistence, preventing exhaustion, and enabling function in hostile tumor microenvironments.
With LYL314 now holding both Fast Track and RMAT designations, Lyell is positioned to accelerate development of this promising therapy for patients with limited treatment options. The company's approach to cell therapy engineering could potentially establish a new standard for CAR T-cell therapy in LBCL and other malignancies.
