Guest Column | September 3, 2026

The Promise Of MRD-Guided CAR-T Treatment

By Zachary Roberts, MD, Ph.D., president and chief executive officer, Allogene Therapeutics

Risk Assessment-GettyImages-2192813165

In large B-cell lymphoma (LBCL), treatment decisions have traditionally been driven by disease that is clinically apparent through scans, biopsies and symptoms. Blood tests, enabling molecular detection of cancer, have the potential to change that paradigm. These tests can reveal minimal residual disease (MRD) before cancer is clinically apparent and create an opportunity for treatment with immediately available cellular therapies, when disease burden is at its lowest. In LBCL, where recurrence after complete remission is seen in approximately one in three patients, that shift could be especially significant.

A growing body of data demonstrates that molecularly detected MRD can persist through clinical remission after first-line (1L) immunochemotherapy and portend relapse in LBCL.1 Recognizing this signal, however, and acting on it are two different things. In LBCL, even with molecular evidence of disease, the current approach is to watch and wait, with patients monitored until clinically apparent disease requires salvage therapy. For patients, that can mean worse clinical outcomes in the face of aggressive disease recurrence, after months or even years of anxiety. For clinicians, it means seeing the warning signal of smoke in the house, but waiting until the house is on fire to act.

Our ALPHA3 trial in LBCL is designed to address this disconnect and change the current treatment paradigm. Instead of watching and waiting, we are enrolling patients who test positive for MRD after finishing treatment into ALPHA3, where we are testing whether acting early — when you smell the smoke — can prevent the disease from ever coming back in the first place.

Early findings encourage our belief that proactive treatment of MRD may be meaningful for patients.

ALPHA3: An Early Signal To Watch

ALPHA3 is the first randomized study in LBCL to test whether acting on MRD for patients in remission at the conclusion of first-line therapy can eliminate residual disease and ultimately prevent clinical relapse.

The design is straightforward. Patients who complete 1L treatment and test MRD-positive are randomized to receive either proactive treatment with a single dose of cemacabtagene ansegedleucel (cema-cel) or, because these patients are at high risk of experiencing recurrence, an enhanced program of observation. The primary endpoint of the study is event free survival (EFS) with the events determined by disease progression, death, or treatment with a new anti-lymphoma agent.

Early in the study, we asked a simple question: can treatment with cema-cel clear the residual disease that patients had when they entered the study? Interim results are promising. ALPHA3 is on the cutting edge of medicine and therefore there is no established threshold for what constitutes a clinically meaningful MRD response. However, literature suggests that an absolute difference of 25%-30% between study arms may be meaningful.2,3,4,5,6 At a protocol-defined 24-patient interim analysis, cema-cel produced a 41.6% absolute improvement (58.3% versus 16.7%) in MRD negativity versus observation at the last MRD assessment prior to the data cut-off. This molecular response induced by cema-cel was also rapid. By the first post-randomization MRD assessment on Day 45, plasma ctDNA had dropped by a median of 97.7% in the cema-cel arm, compared with a median 26.6% increase in molecular disease progression in the observation arm. Notably, these signals emerged despite ALPHA3 enrolling patients with aggressive disease features, including patients with advanced-stage disease, high international prognostic index (IPI) scores, and double- and triple-hit lymphomas.

We should be clear about where we are. This is a small, early data set – 24 patients – and the trial's primary endpoint, EFS, remains blinded. We anticipate an interim EFS analysis in mid-2027 and the primary analysis in 2028. We have more work to do, but an early encouraging signal is meaningful, especially when paired with the safety findings.

Community Delivery, Access, And Safety

Roughly 80% of patients with cancer receive their care in the community, rather than at major academic medical centers.7 Yet CAR T cell therapies like Yescarta and Breyanzi are only available at advanced treatment centers, which serve a small minority of patients.

From the outset, ALPHA3 has been designed to deliver CAR-T broadly. Unlike many CAR-T trials conducted primarily at academic centers with established cell therapy programs, ALPHA3 is open at many community cancer centers, including sites that have never been able to offer CAR-T therapy to their patients. According to the interim analysis, about a third of the screening activity and cema-cel infusions took place at community cancer centers where patients actually receive their care.

Beyond where CAR-T can be delivered, timely access to treatment remains another major challenge. For patients with lymphoma, a relapse is an especially life-threatening event for which the current standard is a high-intensity treatment with CAR T cell therapies like Yescarta and Breyanzi. The referral process, collection of cells from the patient to make the product, and custom manufacturing process can add three to four months between disease recurrence and product infusion.8 Many patients simply don’t have that much time before their disease is out of control.

Cema-cel, as an off-the-shelf agent, removes the complexity of patient-specific cell collection and manufacturing; patients have initiated treatment with the cema-cel regimen in a median of two days after enrolling in earlier Phase 1 studies.9 This creates the potential to substantially reduce one of the major barriers to timely CAR-T treatment.

Even when access and logistics can be addressed, safety remains an important barrier to broader CAR-T use in the community. Side effects of autologous CAR-T make it difficult to bring these treatments into community practices at scale. Initial evidence from the ALPHA3 interim analysis suggests that safety concerns may also be mitigated with cema-cel when there is only MRD to treat.

As of the data cutoff for the interim analysis, the favorable safety profile of cema-cel is encouraging for a CAR-T therapy across both academic and community treatment centers. There have been no cases of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), graft-versus-host disease (GvHD), or treatment-related hospitalizations. In the broader CAR-T experience, as many as 75% or more of patients with lymphoma who receive autologous CAR-T, including those who were intended for outpatient treatment, require hospitalization for toxicity management.10,11 This safety profile opens the door for cema-cel to be used at centers that are not set up to administer autologous CAR-T due to the intensive follow-up required after treatment. A therapy cannot move beyond specialized academic centers unless it can be administered and managed in a broader range of treatment settings.

An allogeneic therapy — manufactured in advance and available when needed — without significant rates of CRS or ICANS has the potential to remove all the major bottlenecks preventing cell therapy from being offered at more treatment settings. ALPHA3 is already beginning to demonstrate what the future of CAR-T therapy could look like in practice.

What This Means For The Field

This is bigger than any one trial or company. The FDA's recent approval of an MRD-guided therapy in bladder cancer showed that molecular detection can do more than predict risk; paired with an effective therapy, it can guide action. That potential of this one-two punch has also been recognized by the FDA, which recently granted Regenerative Medicine Advanced Therapy (RMAT) and Fast Track designations to cema-cel for the treatment of adult patients with LBCL who, at the completion of 1L therapy, are in complete or partial response suitable for observation but test positive for MRD.

Off-the-shelf CAR-T may be particularly well suited to this treatment setting. It is a one-time treatment, immediately available when needed, and introduces healthy donor T cells at a point when the patient’s own lymphocytes have already been depleted by chemotherapy. If we are going to intervene at the MRD stage across a broad population, the therapy has to be ready when and where the patients need it.

This would be a fundamental change to how CAR-T is delivered: not as a bespoke product available at a limited number of centers but as a readily available therapy that reaches patients in their communities. Important questions remain, and maturing data will tell a more complete story, but the direction is becoming clear.

Through the ALPHA3 study, allogeneic CAR-T has a path to demonstrate itself both safe and effective in a treatment setting where its unique advantages matter most. If MRD can tell us when to act, and off-the-shelf CAR-T gives us a practical way to act quickly and safely, we have an opportunity to treat before overt relapse, rather than waiting for it to occur. That would represent a meaningful next chapter for patients and their oncology care.

References:

  1. Roschewski M, Kurtz DM, Westin JR, et al. Remission assessment by circulating tumor DNA in large B-cell lymphoma. J Clin Oncol. 2025;43(34):3652-3661. doi:10.1200/JCO-25-01534.
  2. Stepan L, Ansari S, Abramson JS, et al. Circulating tumor DNA assessment of disease response in large B-cell lymphoma: lisocabtagene maraleucel versus autologous stem cell transplantation standard therapy. J Clin Oncol. 2026;44(19):1767-1773. doi:10.1200/JCO-25-03051..
  3. Kamdar M, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel versus standard of care for second-line relapsed/refractory large B-cell lymphoma: 3-year follow-up from the randomized, phase III TRANSFORM study. J Clin Oncol. 2025;43(24):2671-2678. doi:10.1200/JCO-25-00399
  4. Powles T, Kann AG, Castellano D, et al.; IMvigor011 Investigators. ctDNA-Guided Adjuvant Atezolizumab in Muscle-Invasive Bladder Cancer. N Engl J Med. 2025;393(24):2395-2408. doi:10.1056/NEJMoa2511885
  5. Westin JR, Oluwole OO, Kersten MJ, et al.; ZUMA-7 Investigators; Kite Members. Survival with Axicabtagene Ciloleucel in Large B-Cell Lymphoma. N Engl J Med. 2023;389(2):148-157. doi:10.1056/NEJMoa2301665
  6. Using Natera’s CLARITY™ MRD assay
  7. Sineshaw HM, Zettler CM, Prescott J, et al. Real-world patient characteristics, treatment patterns, and treatment outcomes of patients with diffuse large B-cell lymphoma by line of therapy. Cancer Med. 2024; 13:e7173. doi:10.1002/cam4.7173
  8. Miguel-Angel Perales, Joseph P. McGuirk, Mark R. Fesen, Jeremy Snider, Blythe Adamson, Anthony J. Proli, Hil Hsu, Babatunde Adedokun, Anik R. Patel; Real-world treatment patterns of patients with large B-cell lymphoma over time and into a post–CAR T approval era. Blood Adv 2026; 10 (15): 5325–5337. doi: https://doi.org/10.1182/bloodadvances.2025019064
  9. Frederick L. Locke et al. Allogeneic Chimeric Antigen Receptor T-Cell Products Cemacabtagene Ansegedleucel/ALLO-501 in Relapsed/Refractory Large B-Cell Lymphoma: Phase I Experience From the ALPHA2/ALPHA Clinical Studies. J Clin Oncol 43, 1695-1705(2025). DOI:10.1200/JCO-24-01933
  10. Linhares Y, Freytes CO, Cherry M, et al. OUTREACH: phase 2 study of lisocabtagene maraleucel as outpatient or inpatient treatment at community sites for R/R LBCL. Blood Advances. 2024;8(23):6114-6126. doi:10.1182/bloodadvances.2024013254.
  11. Furqan F, Bhatlapenumarthi V, Dhakal B, et al. Outpatient administration of CAR T-cell therapies using a strategy of no remote monitoring and early CRS intervention. Blood Adv. 2024;8(16):4320-4329. doi:10.1182/bloodadvances.2024013239.

About The Author:

Zachary Roberts, MD, Ph.D., is chief executive officer at Allogene Therapeutics, a role he assumed in July 2026. He was Allogene's executive vice president of research and development and chief medical officer before that. Previously, he was chief medical officer at Instil Bio, and before that, vice president of clinical development at Kite Pharma. He received his medical degree and Ph.D. from the University of Maryland School of Medicine.