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<p>Non-viral engineering can ease CAR-T cell production and reduce regulatory and cost requirements. We utilized Sleeping Beauty transposon to engineer donor-derived anti-CD19.CD28.OX40.CD3zeta T cells differentiated in cytokine-induced killer (CARCIK-CD19) for B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients relapsed after allogeneic hematopoietic stem cell transplantation (alloHSCT). We report the results of CARCIK-CD19 observed in 36 patients (4 children and 32 adults) treated according to the final recommended dose. Cytokine release syndrome of grade 2 or lower occurred in 15 patients, ICANS grade 2 in 1 patient, and late-onset peripheral neurotoxicity of grade 3 in 2 patients. GVHD never occurred after treatment with allogeneic CARCIK-CD19. Complete remission was achieved by 30 out of 36 patients (83.3%), with MRD negativity in 89% of responders. With a median follow-up of 2.2 years, the 1-year overall survival was 57.0%, and event-free survival was 32.0%. The median duration of response at 1 year was 38.6%. CAR-T cells expanded rapidly after infusion and remained detectable for over 2 years. Integration site analysis after infusion showed a high clonal diversity. These data demonstrated that SB-engineered CAR-T cells are safe and induce durable remission in heavily pretreated patients with BCP-ALL relapsed after alloHSCT. Trial registration: The phase 1/2 and phase II trials are registered at <a href="http://www.clinicaltrials.gov">www.clinicaltrials.gov</a> as NCT#03389035 and NCT#05252403.</p>

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Donor-derived CARCIK-CD19 cells engineered with Sleeping Beauty transposon in acute lymphoblastic leukemia relapsed after allogeneic transplantation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月3日

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  • Federico Lussana,
  • Chiara F. Magnani,
  • Stefania Galimberti,
  • Giuseppe Gritti,
  • Giuseppe Gaipa,
  • Daniela Belotti,
  • Benedetta Cabiati,
  • Sara Napolitano,
  • Silvia Ferrari,
  • Alex Moretti,
  • Chiara Buracchi,
  • Gian Maria Borleri,
  • Benedetta Rambaldi,
  • Giuliana Rizzuto,
  • Anna Grassi,
  • Muriel Paganessi,
  • Cristian Meli,
  • Sarah Tettamanti,
  • Giulia Risca,
  • Giulia Pais,
  • Giulio Spinozzi,
  • Fabrizio Benedicenti,
  • Giovanni Cazzaniga,
  • Chiara Capelli,
  • Elisa Gotti,
  • Martino Introna,
  • Josée Golay,
  • Eugenio Montini,
  • Adriana Balduzzi,
  • Maria Grazia Valsecchi,
  • Giuseppe Dastoli,
  • Alessandro Rambaldi,
  • Andrea Biondi

摘要

Non-viral engineering can ease CAR-T cell production and reduce regulatory and cost requirements. We utilized Sleeping Beauty transposon to engineer donor-derived anti-CD19.CD28.OX40.CD3zeta T cells differentiated in cytokine-induced killer (CARCIK-CD19) for B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients relapsed after allogeneic hematopoietic stem cell transplantation (alloHSCT). We report the results of CARCIK-CD19 observed in 36 patients (4 children and 32 adults) treated according to the final recommended dose. Cytokine release syndrome of grade 2 or lower occurred in 15 patients, ICANS grade 2 in 1 patient, and late-onset peripheral neurotoxicity of grade 3 in 2 patients. GVHD never occurred after treatment with allogeneic CARCIK-CD19. Complete remission was achieved by 30 out of 36 patients (83.3%), with MRD negativity in 89% of responders. With a median follow-up of 2.2 years, the 1-year overall survival was 57.0%, and event-free survival was 32.0%. The median duration of response at 1 year was 38.6%. CAR-T cells expanded rapidly after infusion and remained detectable for over 2 years. Integration site analysis after infusion showed a high clonal diversity. These data demonstrated that SB-engineered CAR-T cells are safe and induce durable remission in heavily pretreated patients with BCP-ALL relapsed after alloHSCT. Trial registration: The phase 1/2 and phase II trials are registered at www.clinicaltrials.gov as NCT#03389035 and NCT#05252403.