title: Phase I study of bromohydrin pyrophosphate (BrHPP, IPH 1101), a Vgamma9Vdelta2 T lymphocyte agonist in patients with solid tumors.
abstract: OBJECTIVE
  Vgamma9Vdelta2 (gammadelta) T lymphocytes, a critical peripheral blood lymphocyte subset, are directly cytotoxic against many solid and hematologic tumor types. Vgamma9Vdelta2 T lymphocytes can be selectively expanded in vivo with BrHPP (IPH1101) and IL-2. The present phase I trial was conducted with the aim of determining the maximum-tolerated dose (MTD) and safety of IPH1101 combined with a low dose of IL-2 in patients with solid tumors.
  
  
  METHODS
  A 1-h intravenous infusion of IPH11 was administered alone at cycle 1, combined with a low dose of SC IL-2 (1 MIU/M(2) d1 to d7) in the subsequent cycles (day 1 every 3 weeks). The dose of IPH1101 was escalated from 200 to 1,800 mg/m(2).
  
  
  RESULTS
  As much as 28 patients with solid tumors underwent a total of 109 treatment cycles. Pharmacodynamics data demonstrate that gammadelta T lymphocyte amplification in humans requires the co-administration of IL-2 and is dependent on IPH 1101 dose. Dose-limiting toxicity occurred in two patients at a dose of 1,800 mg/m(2): one grade 3 fever (1 patient) and one grade 3 hypotension (1 patient) suggesting cytokine release syndrome immediately following the first infusion. At lower doses the treatment was well tolerated; the most frequent adverse events were mild fever, chills and abdominal pain, without exacerbation in the IL-2 combined cycles.
  
  
  CONCLUSIONS
  IPH1101 in combination with SC low-dose IL-2 is safe, well tolerated and induces a potent gammadelta T lymphocyte expansion in patients. Its clinical activity will be evaluated in phase II clinical trials.
authors.affiliation: Department of Medical Oncology, Centre René Gauducheau, 44805, Nantes-Saint-Herblain, France. j-bennouna@nantes.fnclcc.fr
authors.forename: Jaafar
authors.initials: J
authors.lastname: Bennouna
authors.forename: Vincent
authors.initials: V
authors.lastname: Levy
authors.forename: Hélène
authors.initials: H
authors.lastname: Sicard
authors.forename: Hélène
authors.initials: H
authors.lastname: Senellart
authors.forename: Marie
authors.initials: M
authors.lastname: Audrain
authors.forename: Sandrine
authors.initials: S
authors.lastname: Hiret
authors.forename: Frédéric
authors.initials: F
authors.lastname: Rolland
authors.forename: Heriberto
authors.initials: H
authors.lastname: Bruzzoni-Giovanelli
authors.forename: Marie
authors.initials: M
authors.lastname: Rimbert
authors.forename: Céline
authors.initials: C
authors.lastname: Galéa
authors.forename: Jérome
authors.initials: J
authors.lastname: Tiollier
authors.forename: Fabien
authors.initials: F
authors.lastname: Calvo
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D011756:Diphosphates / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000145:classification / Q000187:drug effects*; D013601:T-Lymphocytes / Q000145:classification / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D011756:Diphosphates; D007376:Interleukin-2; C429553:bromohydrin pyrophosphate