Novel Booster Infusions Reactivate CAR-T Cells, Prevent Relapse

Roxanne Nelson, RN, BSN

December 16, 2019

ORLANDO, Florida — "Booster" infusions of a second T-cell product may prevent relapse in patients who have been treated with chimeric antigen receptor (CAR) T cells, according to new findings from a small cohort.

These "booster" infusions, containing T cell antigen-presenting cells (T-APCs), were found to be safe, and the majority of treated patients maintained CAR-T cell persistence past day 63.

"This first-in-human study of CD19t T-APCs demonstrates the ability to successfully manufacture T-APCs from stored apheresis products collected for CAR-T cell production," said lead author Colleen Annesley, MD, attending physician at Seattle Children's Hospital and assistant professor in the Department of Pediatrics at the University of Washington.

"Early evidence of efficacy demonstrated by secondary expansion of CAR-T cells suggests the potential of CD19t T-APCs to enhance durable CD19 CAR-T cell persistence and hopefully more durable remissions," she noted.

Annesley presented the results of the study here at the annual meeting of the American Society of Hematology.

CAR-T cell therapy has been hailed as a game changer in the treatment of children and young adults with relapsed or refractory acute lymphoblastic leukemia (ALL).

Annesley noted that, in a clinical trial at her institution, nearly all patients (93%) achieved a minimum residual disease (MRD), but then "relapse does occur in about half of patients."

The early loss of CAR-T cell persistence, defined as that which occurs prior to day 63 after infusion, was associated with increased risk of CD19+ relapse. Low CD19 antigen burden and rapid contraction of CAR-T cells are predictive of early loss of CAR-T cell persistence, explained Annesley. 

Patients with a low CD19 antigen burden (<15% total CD19 in marrow prior to lymphodepletion) had inferior CAR-T cell functional persistence that was demonstrated by B cell aplasia. In addition, patients who had a rapid early contraction of CAR-T cells in peripheral blood between day 10 and 14 were also likely to experience early loss of functional persistence.

Feasible and Safe

The new study, a phase 1 pilot trial known as PLAT-03, examined the feasibility and safety of administering a second T-cell product intended to increase the long-term persistence of the CAR-T cells.

Annesley and colleagues hypothesized that episodic antigen exposure using T-APCs could trigger CD19 CAR-T cell proliferation and reactivation in vivo, which would result in more durable CAR-T cell persistence and diminished risk of CD19+ relapse.

A total of 14 patients between ages 8 and 26 years have been enrolled in the study to date. Of this group, 8 had a low CD19 antigen burden, 5 with rapid CAR-T cell contraction, and 1 patient had experienced early loss of CAR-T cell persistence on a predecessor study and had a re-infusion of CD19 CAR-T cells, which was then followed by T-APCs.

While T-APCs were successfully manufactured in all 14 participants, two lost CAR-T cell persistence before receiving their T-APC infusion and were ineligible to continue. The final cohort included 12 patients who received at least one dose of T-APCs.

Among the 11 patients with low CD19 antigen burden or rapid T cell contraction, 9 had CAR-T cell persistence beyond day 63, as evidenced by B cell aplasia. At the last follow-up, 5 patients had ongoing B cell aplasia, with a median follow up of 13.6 months. Three patients relapsed with a CD19 relapse, and the estimated 1-year leukemia-free survival was 71%.

"In 3 patients, there was a higher numerical value of CAR-T cells in their peripheral blood following a dose of T-APCs than experienced after their initial T-cell infusion," said Annesley.

One patient experienced a grade 3 febrile infusion reaction within hours of the second dose of T-APCs, and further dosing was halted. No other related adverse events above grade 2 were observed, and there were no cases of cytokine release syndrome or neurotoxicity.

The PLAT-03 trial is one of several trials at Seattle Children’s Hospital that aim to improve the long-term efficacy of T-cell immunotherapy. Researchers are also exploring this approach in pediatric patients with neuroblastoma, and hope to expand to other solid tumors.

Annesley has disclosed no relevant financial relationships. Study coauthor Rebecca Gardner reports receiving honoraria from Novartis. Study coauthor Michael C. Jensen reports receiving research funding from Bluebird Bio and Juno Therapeutics.

American Society of Hematology (ASH) 2019. Abstract 223. Presented December 7, 2019.

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