title: Failure to define window of time for autologous tumor vaccination in patients with newly diagnosed or relapsed acute lymphoblastic leukemia.
abstract: OBJECTIVE
  We and others have shown that B cell precursor acute lymphoblastic leukemia cells (ALL) stimulated with CD40 ligand become efficient antigen-presenting cells (APC) capable of expanding autologous, tumor-specific T cells from patients. Translation of these preclinical findings to a novel treatment strategy required four separate issues to be determined: (1) if a CD40-ALL vaccine could be generated for clinical use; (2) whether clinical translation could be achieved; (3) whether the vaccination was safe; and (4) whether a window of time could be identified that would optimize the efficacy of vaccination.
  
  
  METHODS
  Nine patients with relapsed/refractory ALL were enrolled in a phase I trial of vaccination with autologous CD40-ALL. Immunologic reconstitution was measured in a separate cohort of 23 patients with newly diagnosed ALL.
  
  
  RESULTS
  We successfully prepared autologous vaccines for all nine patients in the phase I trial. CD40-ALL were potent APC, capable of stimulating allogeneic and peptide-specific T cells in vitro. Two patients were vaccinated without adverse events. Five patients died or progressed before vaccination, suggesting that rapid disease progression limits vaccination in patients with relapse disease, thus limiting clinical translation. We therefore sought to identify a window of time for vaccination during which this approach might be feasible. To achieve this end, we evaluated immunological reconstitution in newly diagnosed patients with ALL patients. Despite recovery of myelopoiesis, most patients had profound defects in T, B, and natural killer (NK) cell numbers that failed to recover at any point during therapy.
  
  
  CONCLUSIONS
  Autologous tumor vaccination at a time of ALL relapse is not feasible. Alternative strategies for immunotherapy of ALL may require ex vivo generation of antigen specific T cells and adoptive therapy.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. nicholas_haining@dfci.harvard.edu
authors.forename: W Nicholas
authors.initials: WN
authors.lastname: Haining
authors.forename: Angelo A
authors.initials: AA
authors.lastname: Cardoso
authors.forename: Heather L
authors.initials: HL
authors.lastname: Keczkemethy
authors.forename: Mark
authors.initials: M
authors.lastname: Fleming
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: DeAngelo
authors.forename: Richard M
authors.initials: RM
authors.lastname: Stone
authors.forename: Ilene
authors.initials: I
authors.lastname: Galinsky
authors.forename: Lewis B
authors.initials: LB
authors.lastname: Silverman
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Sallan
authors.forename: Lee M
authors.initials: LM
authors.lastname: Nadler
authors.forename: Eva C
authors.initials: EC
authors.lastname: Guinan
mesh_terms: D000293:Adolescent; D000328:Adult; D000938:Antigen-Presenting Cells / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000276:immunology / Q000628:therapy*; D055502:Secondary Prevention; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D013997:Time Factors
chemical_list: D019013:CD40 Antigens; D019496:Cancer Vaccines