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Autologous HER2-specific CAR T cells after lymphodepletion for advanced sarcoma: a phase 1 trial.

Meenakshi HegdeShoba A NavaiChristopher DeRenzoSujith K JosephKhaled SanberMengfen WuAhmed Z GadKatherine A JanewayMatthew CampbellDolores MullikinZeid NawasCatherine RobertsonPretty R MathewHuimin ZhangBirju MehtaRaksha R BhatAngela MajorAnkita ShreeClaudia GerkenMamta KalraRikhia ChakrabortySachin G ThakkarOlga DakhovaVita S SalsmanBambi GrilleyNatalia LaptevaAdrian GeeGianpietro DottiRiyue BaoAhmed Hamed SalemNicholas WangMalcolm K BrennerHelen E HeslopWinfried S WelsM John HicksStephen GottschalkNabil M Ahmed
Published in: Nature cancer (2024)
In this prospective, interventional phase 1 study for individuals with advanced sarcoma, we infused autologous HER2-specific chimeric antigen receptor T cells (HER2 CAR T cells) after lymphodepletion with fludarabine (Flu) ± cyclophosphamide (Cy): 1 × 10 8 T cells per m 2 after Flu (cohort A) or Flu/Cy (cohort B) and 1 × 10 8 CAR + T cells per m 2 after Flu/Cy (cohort C). The primary outcome was assessment of safety of one dose of HER2 CAR T cells after lymphodepletion. Determination of antitumor responses was the secondary outcome. Thirteen individuals were treated in 14 enrollments, and seven received multiple infusions. HER2 CAR T cells expanded after 19 of 21 infusions. Nine of 12 individuals in cohorts A and B developed grade 1-2 cytokine release syndrome. Two individuals in cohort C experienced dose-limiting toxicity with grade 3-4 cytokine release syndrome. Antitumor activity was observed with clinical benefit in 50% of individuals treated. The tumor samples analyzed showed spatial heterogeneity of immune cells and clustering by sarcoma type and by treatment response. Our results affirm HER2 as a CAR T cell target and demonstrate the safety of this therapeutic approach in sarcoma. ClinicalTrials.gov registration: NCT00902044 .
Keyphrases
  • bone marrow
  • induced apoptosis
  • cell therapy
  • oxidative stress
  • high dose
  • open label
  • clinical trial
  • platelet rich plasma
  • cell cycle arrest
  • solid phase extraction