On September 3, 2025 Lyell Immunopharma, Inc. (Nasdaq: LYEL), a late-stage clinical company advancing next-generation CAR T-cell therapies for patients with cancer, reported the initiation of PiNACLE – H2H, a Phase 3 head-to-head CAR T-cell therapy randomized controlled trial and the formation of a Steering Committee of preeminent lymphoma experts (Press release, Lyell Immunopharma, SEP 3, 2025, View Source [SID1234655730]). The trial is evaluating rondecabtagene autoleucel (ronde-cel, also known as LYL314) compared to lisocabtagene maraleucel (liso-cel) or axicabtagene ciloleucel (axi-cel) for the treatment of patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) receiving treatment in the 2L setting. Ronde-cel is an autologous dual-targeting CD19/CD20 chimeric antigen receptor (CAR) T-cell product candidate with Regenerative Medicine Advanced Therapy (RMAT) and Fast Track designations from the U.S. Food and Drug Administration (FDA) for development in patients with R/R LBCL. Ronde-cel targets B cells that express either CD19, CD20, or both, and is manufactured to produce a product with higher proportions of naïve and central memory T cells – features that are designed to deliver improved complete response rates and durability for patients.
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"We believe, based on the robust emerging clinical profile demonstrated by ronde-cel in the Phase 1/2 trial, that targeting both CD19 and CD20 with full potency can deliver more complete responses and prolong the duration of remission as compared to the single antigen-targeting CD19 CAR T-cell therapies currently approved for patients with aggressive large B-cell lymphoma," said David Shook, MD, Lyell’s Chief Medical Officer. "We are delighted to be collaborating with a distinguished group of lymphoma and cell therapy experts on the design and conduct of our ground-breaking head-to-head clinical trial and expect to begin enrolling patients by early 2026."
"Lyell is undertaking a well-designed and innovative Phase 3 trial to provide patients and their physicians with the data needed to demonstrate the potential clinical benefit of ronde-cel, a dual-targeting CD19/CD20 CAR T-cell therapy, over and above that of the currently approved CD19 CAR T-cell therapies," said Michael Jain, MD, PhD, PiNACLE – H2H Steering Committee member and Immune Cell Therapy Medical Director in the Moffitt Cancer Center Department of Blood and Marrow Transplant and Cellular Immunotherapy. "I am encouraged by the promising data from the Phase 1/2 clinical trial of ronde-cel and believe this innovative cell therapy can improve clinical outcomes for patients."
"Lyell is leading the field with the announcement of the first Phase 3 head-to-head CAR T-cell therapy trial for patients with large B-cell lymphoma," said Matthew Lunning, DO, PiNACLE – H2H Steering Committee member and Professor in the Division of Hematology/Oncology at the University of Nebraska Medical Center. "We have designed this trial evaluating ronde-cel to include the spectrum of patients who are currently receiving CD19 CAR T-cell therapy in the large B-cell lymphoma setting, as well as to provide the option for treatment in the outpatient setting based on the safety profile observed to date."
Members of the PiNACLE – H2H Steering Committee include:
Michael Bishop, MD, Professor of Medicine and Director, Hematology/Oncology Cellular Therapy Program, University of Chicago, Chicago, IL
Michael Jain, MD, PhD, Immune Cell Therapy Medical Director in the Moffitt Cancer Center Department of Blood and Marrow Transplant and Cellular Immunotherapy, Tampa, FL
Manali Kamdar, MD, Associate Professor of Medicine and Hematology and Clinical Director of Lymphoma Services, University of Colorado, Denver, CO
Matthew Lunning, DO, Professor in the Division of Hematology/Oncology and Medical Director of Cellular Therapy at the University of Nebraska Medical Center, Omaha, NE
Krish Patel, MD, Director of Lymphoma Research at Sarah Cannon Research Institute (SCRI), Nashville, TN
Jason Westin, MD, Professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
Lyell is advancing two pivotal trials for patients with R/R LBCL:
PiNACLE – H2H is a Phase 3 head-to-head CAR T-cell therapy randomized controlled clinical trial of ronde-cel versus investigator’s choice of either liso-cel or axi-cel in patients with R/R LBCL receiving treatment in the 2L setting. Patients randomized to ronde-cel will be treated with a dose of 100 x 106 CAR T cells. The primary endpoint of the trial is event-free survival. The trial is expected to enroll approximately 400 patients with R/R LBCL, including diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, high grade B-cell lymphoma, grade 3B follicular lymphoma, or transformed follicular or transformed mantle cell lymphoma who have not previously received CAR T-cell therapy. Patients may be treated with ronde-cel in either the inpatient or outpatient setting and are required to remain near the treating center for 14 days. Clinical site initiation is underway in the United States and Australia, and the first patient is expected to be enrolled by early 2026.
PiNACLE is a single-arm pivotal trial of ronde-cel that is enrolling patients with R/R LBCL receiving treatment in the third- or later-line (3L+) setting. This trial is a seamless expansion of the 3L+ cohort of the Phase 1/2 trial of ronde-cel and is expected to enroll approximately 120 patients. The primary endpoint is overall response rate.
About Rondecabtagene Autoleucel (Ronde-cel)
Rondecabtagene autoleucel (ronde-cel, also known as LYL314) is a next-generation dual-targeting CD19/CD20 CAR T-cell product candidate designed to increase complete response rates and prolong the duration of the responses as compared to the approved CD19‑targeted CAR T-cell therapies for the treatment of R/R LBCL.
Ronde-cel is designed with an ‘OR’ logic gate to target B cells that express either CD19, CD20 or both, each with full potency. Ronde-cel is manufactured to produce a CAR T-cell product with higher proportions of naïve and central memory T cells through a proprietary process that enriches for CD62L-expressing cells. This manufacturing process is designed to generate CAR T cells with enhanced antitumor activity.
Ronde-cel has received RMAT designation, as well as Fast Track Designation, from the FDA for the treatment of patients with R/R LBCL in the 3L+ setting.