Risk factors for CAR T-cell manufacturing failure and patient outcomes in large B-cell lymphoma: a report from the UK National CAR T Panel.

in Blood cancer journal by Vaishali Dulobdas, Amy A Kirkwood, Fabio Serpenti, Brijesh Gautama, Aikaterini Panopoulou, Amrith Mathew, Sumantha Gabriel, Ram Malladi, Jessica Pealing, Denise Bonney, Emma Nicholson, Caroline Besley, Sara Ghorashian, Andrea Kuhnl, Elizabeth Davies, Jackie Chappell, Anne Black, Tobias Menne, Maeve A O'Reilly, Robin Sanderson, Sridhar Chaganti

TLDR

  • A retrospective review of 981 patient records found that prior bendamustine therapy within 6 months was associated with CAR T-cell manufacturing failure risk, and remanufacturing led to infusion of a product in-specification in approximately 50% of cases.

Abstract

CAR T-cell manufacturing failure (MF) is a situation where the manufacturing process fails to yield a product or results in one which is out-of-specification (OOS). We conducted a multicentre retrospective review of factors contributing to MF and patient outcomes. Of 981 large B-cell lymphoma (LBCL) patients approved for CAR T-cell therapy, 38 (3.87%) had MF. Eleven patients received delayed infusion with a product in-specification (delayed-infused) following 21 remanufacturing attempts. OOS product was infused in 13 (OOS-infused), and 14 were not infused. For comparison, we included 38 LBCL controls without MF; 29 received infusion (controls-infused). Prior bendamustine was the only baseline variable associated with MF risk, largely due to therapy within 6 months; 23.7% MF vs 0% controls (P = 0.0029). Overall survival (OS) and progression-free survival (PFS) were not significantly different for infused patients, with 1-year OS (PFS) of 52.8% (46.2%), 46.8% (24.2%) and 68.4% (41.4%) for OOS-infused, delayed-infused and controls-infused respectively (PFS HR OOS-infused vs controls-infused 1.41, P = 0.40; delayed-infused vs controls-infused 1.64, P = 0.25; and OOS-infused vs delayed-infused 0.86, P = 0.76). CRS, ICANS and cytopenias were not significantly different between cohorts. Outcomes for OOS-infused LBCL patients following MF are encouraging. Remanufacturing led to infusion of a product in-specification in around 50% and may be an option for patients where a suitable OOS product is not available.

Overview

  • The study aimed to investigate factors contributing to CAR T-cell manufacturing failure (MF) and patient outcomes in large B-cell lymphoma (LBCL) patients.
  • A retrospective review of 981 patient records revealed 38 cases of MF, with 11 patients receiving a remanufactured product, 13 receiving OOS product, and 14 not receiving infusion.
  • The primary objective was to identify factors associated with MF risk and patient outcomes after MF and to explore the efficacy of remanufacturing.

Comparative Analysis & Findings

  • Prior bendamustine therapy within 6 months was the only baseline variable associated with MF risk, with 23.7% of patients experiencing MF compared to 0% of controls (P = 0.0029).
  • Overall survival (OS) and progression-free survival (PFS) were not significantly different between infused patients, with 1-year OS (PFS) rates ranging from 24.2% to 68.4% (PFS HR OOS-infused vs controls-infused 1.41, P = 0.40).
  • Cytopenias, CRS, and ICANS were not significantly different between cohorts.

Implications and Future Directions

  • Remanufacturing led to infusion of a product in-specification in approximately 50% of cases and may be an option for patients where a suitable OOS product is not available.
  • The study highlights the need for improved process controls and quality assurance measures to reduce MF events and improve patient outcomes.
  • Future studies should investigate the optimal duration of bendamustine therapy before CAR T-cell infusion to minimize MF risk.
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