title: Leukemia cell-rhabdovirus vaccine: personalized immunotherapy for acute lymphoblastic leukemia.
abstract: OBJECTIVE
  Acute lymphoblastic leukemia (ALL) remains incurable in most adults. It has been difficult to provide effective immunotherapy to improve outcomes for the majority of patients. Rhabdoviruses induce strong antiviral immune responses. We hypothesized that mice administered ex vivo rhabdovirus-infected ALL cells [immunotherapy by leukemia-oncotropic virus (iLOV)] would develop robust antileukemic immune responses capable of controlling ALL.
  
  
  METHODS
  Viral protein production, replication, and cytopathy were measured in human and murine ALL cells exposed to attenuated rhabdovirus. Survival following injection of graded amounts of ALL cells was compared between cohorts of mice administered γ-irradiated rhabdovirus-infected ALL cells (iLOV) or multiple control vaccines to determine key immunotherapeutic components and characteristics. Host immune requirements were assessed in immunodeficient and bone marrow-transplanted mice or by adoptive splenocyte transfer from immunized donors. Antileukemic immune memory was ascertained by second leukemic challenge in long-term survivors.
  
  
  RESULTS
  Human and murine ALL cells were infected and killed by rhabdovirus; this produced a potent antileukemia vaccine. iLOV protected mice from otherwise lethal ALL by developing durable leukemia-specific immune-mediated responses (P < 0.0001), which required an intact CTL compartment. Preexisting antiviral immunity augmented iLOV potency. Splenocytes from iLOV-vaccinated donors protected 60% of naïve recipients from ALL challenge (P = 0.0001). Injecting leukemia cells activated by, or concurrent with, multiple Toll-like receptor agonists could not reproduce the protective effect of iLOV. Similarly, injecting uninfected irradiated viable, apoptotic, or necrotic leukemia cells with/without concurrent rhabdovirus administration was ineffective.
  
  
  CONCLUSIONS
  Rhabdovirus-infected leukemia cells can be used to produce a vaccine that induces robust specific immunity against aggressive leukemia.
authors.affiliation: Ottawa Hospital Research Institute, Center for Cancer Therapeutics, Ottawa, Ontario, Canada.
authors.forename: David P
authors.initials: DP
authors.lastname: Conrad
authors.forename: Jovian
authors.initials: J
authors.lastname: Tsang
authors.forename: Meaghan
authors.initials: M
authors.lastname: Maclean
authors.forename: Jean-Simon
authors.initials: JS
authors.lastname: Diallo
authors.forename: Fabrice
authors.initials: F
authors.lastname: Le Boeuf
authors.forename: Chantal G
authors.initials: CG
authors.lastname: Lemay
authors.forename: Theresa J
authors.initials: TJ
authors.lastname: Falls
authors.forename: Kelley A
authors.initials: KA
authors.lastname: Parato
authors.forename: John C
authors.initials: JC
authors.lastname: Bell
authors.forename: Harold L
authors.initials: HL
authors.lastname: Atkins
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D016026:Bone Marrow Transplantation; D019496:Cancer Vaccines; D045744:Cell Line, Tumor; D002470:Cell Survival; D002522:Chlorocebus aethiops; D006801:Humans; D016219:Immunotherapy, Adoptive; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D057285:Precision Medicine; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology / Q000628:therapy*; D012209:Rhabdoviridae / Q000502:physiology*; D014709:Vero Cells
chemical_list: D019496:Cancer Vaccines