title: Local and systemic effects of an allogeneic tumor cell vaccine combining transgenic human lymphotactin with interleukin-2 in patients with advanced or refractory neuroblastoma.
abstract: In murine models, transgenic chemokine-cytokine tumor vaccines overcome many of the limitations of single-agent immunotherapy by producing the sequence of T-cell attraction followed by proliferation. The safety and immunologic effects of this approach in humans were tested in 21 patients with relapsed or refractory neuroblastoma. They received up to 8 subcutaneous injections of a vaccine combining lymphotactin (Lptn)- and interleukin-2 (IL-2)-secreting allogeneic neuroblastoma cells in a dose-escalating scheme. Severe adverse reactions were limited to reversible panniculitis in 5 patients and bone pain in 1 patient. Injection-site biopsies revealed increased cellularity caused by infiltration of CD4+ and CD8+ lymphocytes, eosinophils, and Langerhans cells. Systemically, the vaccine produced a 2-fold (P =.035) expansion of CD4+ T cells, a 3.5-fold (P =.039) expansion of natural killer (NK) cells, a 2.1-fold (P =.014) expansion of eosinophils, and a 1.6-fold (P =.049) increase in serum IL-5. When restimulated in vitro by the immunizing cell line, T cells collected after vaccination showed a 2.3-fold increase (P =.02) of T-helper (TH2)-type CD3+IL-4+ cells. Supernatant collected from restimulated cells showed increased amounts of IL-4 (11.4-fold; P =.021) and IL-5 (8.7-fold; P =.002). Six patients had significant increases in NK cytolytic activity. Fifteen patients made immunoglobulin G (IgG) antibodies that bound to the immunizing cell line. Measurable tumor responses included complete remission in 2 patients and partial response in 1 patient. Hence, allogeneic tumor cell vaccines combining transgenic Lptn with IL-2 appear to have little toxicity in humans and can induce an antitumor immune response.
authors.affiliation: Center for Cell and Gene Therapy, Texas Children's Cancer Center, and the Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA. rfrousse@txccc.org
authors.forename: Raphaël F
authors.initials: RF
authors.lastname: Rousseau
authors.forename: Ann E
authors.initials: AE
authors.lastname: Haight
authors.forename: Charlotte
authors.initials: C
authors.lastname: Hirschmann-Jax
authors.forename: Eric S
authors.initials: ES
authors.lastname: Yvon
authors.forename: Donna R
authors.initials: DR
authors.lastname: Rill
authors.forename: Zhuyong
authors.initials: Z
authors.lastname: Mei
authors.forename: Susan C
authors.initials: SC
authors.lastname: Smith
authors.forename: Shannon
authors.initials: S
authors.lastname: Inman
authors.forename: Kristine
authors.initials: K
authors.lastname: Cooper
authors.forename: Pat
authors.initials: P
authors.lastname: Alcoser
authors.forename: Bambi
authors.initials: B
authors.lastname: Grilley
authors.forename: Adrian
authors.initials: A
authors.lastname: Gee
authors.forename: Edwina
authors.initials: E
authors.lastname: Popek
authors.forename: Andrew
authors.initials: A
authors.lastname: Davidoff
authors.forename: Laura C
authors.initials: LC
authors.lastname: Bowman
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Brenner
authors.forename: Douglas
authors.initials: D
authors.lastname: Strother
mesh_terms: D000293:Adolescent; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000009:adverse effects / Q000627:therapeutic use*; D019744:Chemokines, C; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000097:blood; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000209:etiology; D007115:Immunization Schedule; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D016130:Immunophenotyping; D007223:Infant; D007279:Injections, Subcutaneous; D007376:Interleukin-2 / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000276:immunology; D008222:Lymphokines / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D008297:Male; D009447:Neuroblastoma / Q000473:pathology / Q000628:therapy*; D015434:Panniculitis / Q000209:etiology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use; D012074:Remission Induction; D016879:Salvage Therapy; D012795:Sialoglycoproteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D012867:Skin / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology; D014161:Transduction, Genetic; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects / Q000637:transplantation
chemical_list: D019496:Cancer Vaccines; D019744:Chemokines, C; D016207:Cytokines; D018076:DNA, Complementary; D007074:Immunoglobulin G; D007376:Interleukin-2; D008222:Lymphokines; D011993:Recombinant Fusion Proteins; D012795:Sialoglycoproteins; C092390:XCL1 protein, human; C018997:lymphotactin