Although available chimeric antigen receptor (CAR) T-cell therapies have revolutionized treatment of blood cancers, accessibility remains limited by complex logistics, time constraints, and personalized manufacturing. Allogene Therapeutics, a clinical-stage biotechnology company in South San Francisco, is rewriting this paradigm with its pioneering allogeneic (AlloCAR T) platform—a scalable, ‘off-the-shelf’ alternative designed to deliver cell therapy faster, more broadly, and at greater consistency than ever before. Today, Allogene is advancing its ALPHA3 trial—the next frontier in allogeneic CAR-T innovation—aimed at not only treating relapse but ultimately preventing it.
Shortcomings of treatment for large B-cell lymphoma
More than 60,000 patients are treated for large B-cell lymphoma (LBCL) annually, across the US, UK and EU. First-line (1L) chemoimmunotherapy cures about 60% of patients, but one in three relapses, often within one year1. For these patients, subsequent treatment options are limited and less effective, and most will die from their disease (Fig. 1).
Fig. 1 | Changing the standard of care. 1L, first-line; 2L, second-line; CAR, chimeric-antigen receptor; LBLC, large B-cell lymphoma; MRD, minimal residual disease.
Despite three approved autologous CAR-T therapies, only about 20% of eligible LBCL patients receive treatment2. Access is constrained by complex manufacturing, limited scalability, and the small number of centers equipped to deliver CAR-T therapy.
Allogene seeks to change this with its lead investigational allogeneic CAR-T product candidate, cemacabtagene ansegedleucel (cema-cel). Early phase trials demonstrated a 67% overall response rate and 58% complete response rate in relapsed/refractory LBCL and a median duration of complete remission extending to 23.1 months3. In the ongoing registrational phase 2 ALPHA3 trial, Allogene aims to demonstrate that giving cema-cel to patients at high risk of relapse after 1L treatment can prevent recurrence.
Traditional imaging cannot detect minimal residual disease (MRD), a strong predictor of relapse after 1L therapy. The current standard of care (SOC) is to follow patients with regular clinic visits and scans until relapse occurs. ALPHA3 uses an innovative MRD blood test that detects circulating tumor DNA to identify patients at greatest risk of relapse following 1L treatment. Patients who are MRD positive are then randomized to SOC (referred to as ‘watch and wait’ or observation) or a single dose of cema-cel.
“Pairing next-generation MRD testing with our investigational allogeneic CAR-T product candidate has the potential to predict and prevent relapse,” said Zachary Roberts, executive vice president of research and development and CMO of Allogene. “By identifying high-risk patients and treating them proactively with an ‘off-the-shelf’ CAR-T product when disease burden is low and their overall health is better, we hope to intercept disease before it advances to improve long-term outcomes.”
According to Jeremy Abramson, professor of medicine at Harvard Medical School and director of the Center for Lymphoma at the Mass General Cancer Center in Boston, Massachusetts, “If this strategy proves successful, we will have addressed one of the most pressing needs in the management of diffuse large B-cell lymphoma today: the ability to identify patients destined to relapse after responding to initial treatment, and to give those patients an immunotherapy to prevent that relapse before it happens.”
Overcoming limitations to broaden access
ALPHA3 could significantly expand access by enabling CAR-T treatment in community cancer centers, where 80% of LBCL patients are treated. This decentralization is possible by the unique attributes of Allogene’s products, which are manufactured in large batches for on-demand treatment, eliminating the need for patient-specific cell collection, weeks- or months-long manufacturing timelines, and specialized logistics. Each manufacturing run can produce 100 or more doses or up to 20,000 doses annually.
“By breaking through access barriers and intervening before relapse occurs, we are pioneering a new model for when, where and how CAR-T therapy can be delivered, and redefining what’s possible in cell therapy,” Roberts said.