What is the rationale for the development of tandem CAR T-cell therapies?

The Lymphoma Hub was pleased to speak with Peter Borchmann, University Hospital Cologne, DE. We asked, What is the rationale for the development of tandem chimeric antigen receptor (CAR) T-cell therapies?

Key points 

• CAR T-cell therapies have revolutionized the treatment of patients with second- or third-line large B-cell lymphoma (LBCL), substantially improving outcomes and enabling durable remission compared with standard salvage immunochemotherapy.^1–3
• Despite these advances, approximately half of patients treated with currently approved CD19-targeted CAR T-cell therapies experience relapse or progression.^4,5
• Heterogeneous expression of B-cell antigens may allow some malignant cells to evade single antigen targeting.⁶
• Antigen escape through loss of CD19 expression is an important mechanism of relapse, with CD19 loss reported in roughly one quarter to one third of patients with LBCL relapsing after CD19-targeted CAR T-cell therapy.^7,8
• Tandem CAR T-cell therapies have therefore been developed to simultaneously target CD19 and an additional antigen, such as CD20, with the aim of reducing antigen-negative relapse and improving the depth and durability of response.⁸
• The phase II DALY 2-EU trial (NCT04844866) assessed the efficacy and safety of zamtocabtagene autoleucel (zamto-cel), an autologous non-cryopreserved, tandem CD20-CD19-directed CAR T-cell therapy vs standard of care rituximab + gemcitabine + oxaliplatin (R-GemOx) in second-line, transplant-ineligible patients with high-risk relapsed/refractory LBCL.⁹
• Zamto-cel is produced in an automated system with a fixed 12-day manufacturing window and an average vein-to-vein time of 14 days.⁹
• In preclinical models, zamto-cel has shown improved efficacy and safety over CD19-targeted CAR T-cell constructs.¹⁰
• In the DALY 2-EU trial, 168 patients were randomized to either zamto-cel or R-GemOx. In the zamto-cel arm:
  • 50% of patients were aged ≥75 years.⁹
  • 31% of patients had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 2.⁹
  • 51% of patients had refractory disease.⁹
  • 57% of patients had an International Prognostic Index (IPI) score of 3–5.⁹
• The primary endpoint was met; after a median follow-up of 17 months, zamto-cel improved event-free survival (EFS) vs R-GemOx (median, 6.21 months vs 2.53 months; hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.27–0.58; p < 0.0001).⁹
• In the intention-to-treat (ITT) population, the objective response rate (ORR) and complete response (CR) rate with zamto-cel were 72% and 54%, respectively, compared with 45% and 14%, respectively, in the R-GemOx arm.⁹
  • In the modified ITT population, the ORR and CR rates with zamto-cel vs R-GemOx were 81% vs 48% and 60% vs 15%, respectively.⁹
• Rates of Grade ≥3 cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) in the zamto-cel arm were 5.3% and 1.3%, respectively.⁹
• These findings were consistent with the preclinical rationale for the tandem CD20-CD19-directed CAR construct, and the favorable risk/benefit profile supports the continued development of zamto-cel as a second-line therapy in patients with R/R LBCL.^9,10
• Several other CAR T-cell therapies targeting both CD19 and CD20 have demonstrated promising initial efficacy, with phase III trials in progress comparing dual-targeted CAR T-cell therapies with CD19-targeted CAR T-cell therapies; these studies may determine whether dual-targeted CAR T-cell therapies can improve outcomes for patients with R/R LBCL.^11,12

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