What is the current clinical evidence for tandem CAR T-cell therapies in R/R DLBCL?

The Lymphoma Hub was pleased to speak to Nirav Shah, Medical College of Wisconsin, Milwaukee, US. We asked, What is the current clinical evidence for tandem chimeric antigen receptor (CAR) T-cell therapies in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL)?

Key points

• CD19-targeted CAR T-cell therapies have transformed the treatment of R/R B-cell lymphomas.¹
• Despite their efficacy, antigen escape through loss of CD19 expression remains a key limitation of single target CAR T-cell therapies.¹
• To overcome this resistance mechanism, tandem CAR T-cell therapies targeting both CD19 and CD20 are currently being investigated, with encouraging initial efficacy.¹
• Zamtocabtagene autoleucel (zamto-cel) is a tandem CD19/CD20-directed non-cryopreserved CAR T-cell therapy currently being assessed in two phase II trials:
  • The multicenter, open-label, randomized DALY 2-EU trial (NCT04844866) compares zamto-cel vs standard of care chemoimmunotherapy in transplant-ineligible patients with large B-cell lymphoma (LBCL) after 1 prior line of therapy.²
  • The multicenter, open-label, single-arm, phase II DALY II USA trial (NCT04792489) is evaluating the efficacy and safety of zamto-cel in patients with R/R DLBCL after ≥2 prior lines of therapy.³
• Primary results from the DALY 2-EU trial showed that, after a median follow-up of 17 months, zamto-cel improved median event-free survival (EFS) vs rituximab + gemcitabine + oxaliplatin (R-GemOx) (6.21 months vs 2.53 months; hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.27–0.58; p < 0.0001).²
  • The safety profile of zamto-cel was manageable, with Grade ≥3 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS) reported in 5.3% and 1.3% of patients, respectively.²
• Interim results from the DALY II USA trial demonstrate favorable outcomes with zamto-cel, with an overall response rate (ORR) and complete response (CR) rate of 70.8% and 50.8%, respectively.³
• Longer follow-up from the DALY 2-EU and DALY II USA trials is necessary to determine how zamto-cel might compare with current CD19-directed CAR T-cell therapies. 
• Rondecabtagene autoleucel (ronde-cel) is a dual-targeted CD19/CD20 CAR T-cell therapy manufactured from CD62L+ enriched naïve and central memory T cells.⁴
• In a phase I/II trial (NCT05826535), ronde-cel has demonstrated encouraging initial efficacy with a manageable safety profile in both second-line and third-line+ DLBCL.⁴ 
  • Based on results from this trial, the randomized, phase III PiNACLE-H2H trial (NCT07188558) has been initiated, comparing ronde-cel vs investigator’s choice of approved CD19 CAR T-cell therapy (axicabtagene autoleucel or lisocabtagene maraleucel) in patients with R/R LBCL in the second-line setting.⁴
• KITE-363, a bicistronic, CD19/CD20 dual-targeting CAR T-cell therapy, is currently being assessed in patients with R/R B-cell lymphoma in the phase I PALISADES-1 trial (NCT04989803).⁵
  • KITE-363 demonstrated promising initial activity, with ORR and CR rates of 87% and 78%, respectively.⁵
• Collectively, these data support the continued development of dual-targeted CAR T-cell therapies as a potential strategy to overcome antigen escape and improve outcomes in patients with DLBCL, although longer follow-up and comparative studies are warranted.

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