Allogene Therapeutics' ALPHA3 trial is investigating a novel approach to treating large B-cell lymphoma (LBCL) by using minimal residual disease (MRD) testing to guide the administration of CAR-T therapy in patients at high risk of relapse. This strategy, born from insights shared at the American Society of Hematology (ASH) annual meeting, aims to improve cure rates and reduce the need for more aggressive treatments upon relapse.
Identifying High-Risk Patients with MRD Testing
The ALPHA3 trial enrolls LBCL patients who have completed first-line treatment but are likely to relapse. Foresight Diagnostics' CLARITY MRD test, which can detect cancer DNA at a rate of less than one part per million, identifies these patients. This ultrasensitive detection allows for the identification of microscopic levels of disease that are undetectable by conventional methods like PET/CT scans.
"Up until this point, ctDNA-MRD hasn’t had the sensitivity required to design a trial such as this because you need to have very high limits of detection in order to adjudicate whether patients actually have the disease or are true negatives," noted John Truesdell, chief business officer of Foresight Diagnostics.
CAR-T Consolidation to Prevent Relapse
Patients who test positive for MRD are eligible for the ALPHA3 trial, where they are randomized to receive either Allogene's CD19-directed CAR-T product candidate, cemacabtagene ansegedleucel (cema-cel), or the current standard of care with close monitoring. The goal is to consolidate remission and prevent relapse by administering CAR-T therapy at the end of first-line treatment.
"If we can come in and mop up that residual disease so that patients never experience that relapse in the first place, that would be a massive step forward for these patients," said Dr. Zachary Roberts, EVP, Research and Development and Chief Medical Officer at Allogene Therapeutics.
Expanding Access to CAR-T Therapy
ALPHA3 utilizes an allogeneic, or "off-the-shelf," CAR-T product, which eliminates the need for extracting and reinfusing a patient's own cells. This approach allows for community-based treatment, expanding access to CAR-T therapy and reducing the burden on patients who would otherwise need to travel to specialized centers.
"Many of the first clinical trial sites have been community oncology practices that have never had a CAR-T program before," Roberts noted. "And these are large network practices who treat hundreds of patients a year. So this is their first time really taking that step in providing access to CAR-T – and they get to keep their patients within the community practice."
Potential Benefits for Patients and the Healthcare System
The ALPHA3 trial offers several potential benefits. Patients who test negative for MRD may gain peace of mind, while those who test positive have the opportunity to receive potentially curative CAR-T therapy. The trial's design also avoids escalating care unnecessarily for patients who would have been cured by first-line treatment alone.
If successful, this strategy could potentially help to reduce overall costs to the healthcare system.
