Lyell Immunopharma Announces the Initiation of a Phase 3 Head-to-Head CAR T-Cell Therapy Clinical Trial in Aggressive Large B-Cell Lymphoma and Formation of Expert Steering Committee
Lyell Immunopharma (Nasdaq: LYEL) has initiated PiNACLE - H2H, a groundbreaking Phase 3 head-to-head CAR T-cell therapy trial comparing rondecabtagene autoleucel (ronde-cel) against approved CD19 CAR T-cell therapies for large B-cell lymphoma (LBCL) in second-line treatment.
Ronde-cel, a dual-targeting CD19/CD20 CAR T-cell therapy with FDA's RMAT and Fast Track designations, is designed to improve complete response rates and durability. The trial will enroll approximately 400 patients starting early 2026, with event-free survival as the primary endpoint.
The company has formed a distinguished Steering Committee of lymphoma experts and is simultaneously advancing a single-arm pivotal trial (PiNACLE) for third-line-plus LBCL treatment, targeting approximately 120 patients.
Lyell Immunopharma (Nasdaq: LYEL) ha avviato PiNACLE - H2H, un innovativo trial di Fase 3 testa a testa su terapie CAR T che confronta rondecabtagene autoleucel (ronde-cel) con le CAR T anti-CD19 approvate per il linfoma a grandi cellule B (LBCL) in seconda linea.
Ronde-cel, una terapia CAR T a doppio targeting CD19/CD20 con designazioni FDA RMAT e Fast Track, è studiata per migliorare i tassi di risposta completa e la loro durata. Lo studio arruolerà circa 400 pazienti a partire dall'inizio del 2026, con la sopravvivenza senza eventi come endpoint primario.
L'azienda ha costituito un distinto Steering Committee di esperti in linfomi e sta parallelamente portando avanti uno studio pivotale a braccio singolo (PiNACLE) per il trattamento di LBCL in terza linea e oltre, con l'obiettivo di arruolare circa 120 pazienti.
Lyell Immunopharma (Nasdaq: LYEL) ha iniciado PiNACLE - H2H, un innovador ensayo fase 3 cara a cara de terapia CAR T que compara rondecabtagene autoleucel (ronde-cel) con las terapias CAR T anti‑CD19 aprobadas para el linfoma de grandes células B (LBCL) en segunda línea.
Ronde-cel, una terapia CAR T de doble diana CD19/CD20 con designaciones FDA RMAT y Fast Track, está diseñada para mejorar las tasas de respuesta completa y su durabilidad. El ensayo reclutará aproximadamente 400 pacientes a partir de principios de 2026, con la supervivencia libre de eventos como endpoint primario.
La compañía ha formado un distinguido Comité Directivo de expertos en linfoma y avanza al mismo tiempo un ensayo pivotal de brazo único (PiNACLE) para el tratamiento de LBCL en tercera línea o más, con una meta de alrededor de 120 pacientes.
Lyell Immunopharma (Nasdaq: LYEL)는 PiNACLE - H2H를 시작했습니다. 이는 rondecabtagene autoleucel(ronde-cel)과 승인된 CD19 CAR T 요법들을 비교하는 획기적인 3상 대조(헤드투헤드) CAR T 세포 치료 임상시험으로, 2차 치료의 대형 B세포 림프종(LBCL)을 대상으로 합니다.
Ronde-cel은 FDA의 RMAT 및 Fast Track 지정을 받은 CD19/CD20 이중 표적 CAR T 세포 치료제로, 완전 관해율과 그 지속성을 개선하도록 설계되었습니다. 이 시험은 2026년 초부터 약 400명을 등록할 예정이며, 주요 평가변수는 무사건 생존기간(event-free survival)입니다.
회사는 림프종 전문가들로 구성된 저명한 운영위원회(Steering Committee)를 구성했으며, 동시에 3차 이상 LBCL 치료를 위한 단일군 피보탈 시험(PiNACLE)을 진행 중으로 약 120명의 환자 등록을 목표로 하고 있습니다.
Lyell Immunopharma (Nasdaq: LYEL) a lancé PiNACLE - H2H, un essai révolutionnaire de Phase 3 en confrontation directe (head‑to‑head) de thérapies CAR‑T comparant le rondecabtagene autoleucel (ronde‑cel) aux thérapies CAR‑T anti‑CD19 approuvées pour le lymphome B à grandes cellules (LBCL) en seconde ligne.
Ronde‑cel, une thérapie CAR‑T ciblant à la fois CD19 et CD20, bénéficiant des désignations FDA RMAT et Fast Track, vise à améliorer les taux de réponse complète et leur durabilité. L'essai recrutera environ 400 patients à partir du début 2026, la survie sans événement étant le critère principal.
La société a constitué un distingué comité directeur (Steering Committee) d'experts en lymphomes et fait simultanément avancer un essai pivot monocentrique (PiNACLE) pour le traitement du LBCL en troisième ligne et au‑delà, visant environ 120 patients.
Lyell Immunopharma (Nasdaq: LYEL) hat PiNACLE - H2H gestartet, eine bahnbrechende Phase‑3 Head‑to‑Head CAR‑T‑Zelltherapie‑Studie, die rondecabtagene autoleucel (ronde‑cel) mit zugelassenen CD19 CAR‑T‑Therapien beim großzelligen B‑Zell‑Lymphom (LBCL) in der Zweitlinientherapie vergleicht.
Ronde‑cel, eine dual zielende CD19/CD20 CAR‑T‑Therapie mit FDA‑Zulassungswegen RMAT und Fast Track, wurde entwickelt, um die Komplettansprechrate und deren Dauer zu verbessern. Die Studie wird ab Anfang 2026 etwa 400 Patienten einschließen, wobei das ereignisfreie Überleben als primärer Endpunkt dient.
Das Unternehmen hat ein renommiertes Steering Committee aus Lymphom‑Experten gebildet und betreibt parallel eine einarmige zulassungsrelevante Studie (PiNACLE) für die Drittlinien‑ und Folgetherapie bei LBCL mit dem Ziel, rund 120 Patienten zu rekrutieren.
- Ronde-cel has received both RMAT and Fast Track designations from FDA
- First-of-its-kind Phase 3 head-to-head CAR T-cell therapy trial
- Dual-targeting mechanism (CD19/CD20) potentially offering improved efficacy
- Flexibility for both inpatient and outpatient treatment settings
- Formation of expert Steering Committee with distinguished lymphoma specialists
- Patient enrollment not starting until early 2026
- Large trial size (400 patients) may extend completion timeline
- Complex trial design requiring 14-day proximity to treatment center
Insights
Lyell's Phase 3 head-to-head trial of dual-targeting CAR-T therapy could reshape LBCL treatment landscape if successful.
Lyell Immunopharma's initiation of the PiNACLE-H2H Phase 3 trial represents a significant milestone in CAR T-cell therapy development for large B-cell lymphoma (LBCL). This is the first head-to-head CAR-T randomized trial in this indication, directly comparing their novel dual-targeting approach against current standard-of-care therapies.
The investigational product, rondecabtagene autoleucel (ronde-cel), incorporates two critical innovations: dual targeting of both CD19 and CD20 antigens, and manufacturing optimized for higher proportions of naïve and central memory T cells. This dual-antigen approach is designed to address a key limitation of current CD19-only CAR-T therapies - antigen escape, where cancer cells evade treatment by downregulating CD19 expression.
The trial's second-line treatment setting is particularly notable, as it positions ronde-cel to potentially capture a larger market than third-line therapies. The 400-patient enrollment target is robust for a cell therapy trial, providing statistical power to detect meaningful differences in the primary endpoint of event-free survival.
The assembled steering committee includes renowned lymphoma experts from major cancer centers, lending scientific credibility to the trial design. The committee's participation signals strong interest from the clinical community.
Importantly, the press release notes that ronde-cel may be administered in either inpatient or outpatient settings with a 14-day monitoring period - potentially offering logistical advantages over therapies requiring longer hospitalization.
With Fast Track and RMAT designations already secured, positive results could accelerate regulatory review. The company appears to be pursuing a comprehensive development strategy with two parallel pivotal trials: this head-to-head study and a single-arm PiNACLE trial in later-line treatment.
- PiNACLE - H2H will evaluate rondecabtagene autoleucel (ronde-cel) versus investigator’s choice of approved CD19 CAR T-cell therapies in patients with aggressive large B-cell lymphoma receiving treatment in the second line (2L) setting
- Ronde-cel is Lyell’s next-generation, dual-targeting CD19/CD20 CAR T-cell therapy designed to deliver improved complete response rates and longer duration of responses over currently approved CD19 CAR T-cell therapies
- Steering Committee of distinguished lymphoma experts established to advise on the design and conduct of this first-of-its-kind CAR T-cell clinical trial
SOUTH SAN FRANCISCO, Calif., Sept. 03, 2025 (GLOBE NEWSWIRE) -- Lyell Immunopharma, Inc. (Nasdaq: LYEL), a late-stage clinical company advancing next-generation CAR T-cell therapies for patients with cancer, today announced 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. 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.
“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.
About Lyell
Lyell is a late-stage clinical company advancing a pipeline of next-generation CAR T-cell therapies for patients with hematologic malignancies and solid tumors. To realize the potential of cell therapy for cancer, Lyell utilizes a suite of technologies to endow CAR T cells with attributes needed to drive durable tumor cytotoxicity and achieve consistent and long-lasting clinical responses, including the ability to resist exhaustion, maintain qualities of durable stemness, and function in the hostile tumor microenvironment. Lyell’s LyFE Manufacturing Center™ has commercial launch capability and can manufacture more than 1,200 CAR T-cell doses at full capacity. To learn more, please visit www.lyell.com.
Forward Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements expressed or implied in this press release include, but are not limited to, statements regarding: the potential clinical benefits and therapeutic potential of ronde-cel for patients with R/R LBCL, including its potential to increase complete response rates and prolong the duration of responses as compared to approved CD19-targeted CAR T-cell therapies for the treatment of LBCL; the potential benefits, if any, from the RMAT and Fast Track designations from the FDA for the treatment of patients with R/R LBCL in the 3L+ setting; statements made by our Chief Medical Officer and members of the PiNACLE – H2H Steering Committee; expectations around enrollment, trial design, dosing and timing of -PiNACLE and PiNACLE H2H; the sufficiency of the capacity of LyFE to manufacture drug supply for Lyell’s ongoing and planned pivotal trials and through potential commercial launch; and other statements that are not historical fact. These statements are based on Lyell’s current plans, objectives, estimates, expectations and intentions, are not guarantees of future performance and inherently involve significant risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties, which include, but are not limited to, risks and uncertainties related to: the potential for results from clinical trials to differ from nonclinical, early clinical, preliminary or expected results; Lyell’s limited experience as a company in enrolling and conducting clinical trials and lack of experience in completing clinical trials; significant adverse events, toxicities or other undesirable side effects associated with Lyell’s product candidates; Lyell’s ability to initiate or progress clinical trials on the anticipated timelines, if at all; RMAT and Fast Track designations may not actually lead to faster development, regulatory review or approval process, and does not assure ultimate FDA approval; the significant uncertainty associated with Lyell’s product candidates ever receiving any regulatory approvals; Lyell’s ability to obtain, maintain or protect intellectual property rights related to its product candidates; the complexity of manufacturing cellular therapies and Lyell’s ability to manufacture and supply its product candidates for its clinical trials; implementation of Lyell’s strategic plans for its business and product candidates; the sufficiency of Lyell’s capital resources and need for additional capital to achieve its goals; the effects of macroeconomic conditions, including the effects of disruption between the U.S. and its trading partners due to tariffs or other policies, and any geopolitical instability; potential changes to U.S. drug pricing, including the potential for “most-favored nations” pricing limitations; and other risks, including general economic conditions and regulatory developments, not within our control; and other risks described under the heading “Risk Factors” in Lyell’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2025, filed with the Securities and Exchange Commission on August 12, 2025. Forward-looking statements contained in this press release are made as of this date, and Lyell undertakes no duty to update such information except as required under applicable law.
Contact:
Ellen Rose
Senior Vice President, Communications and Investor Relations
erose@lyell.com
FAQ
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