title: A phase-I clinical study of autologous tumor cells plus interleukin-2-gene-transfected allogeneic fibroblasts as a vaccine in patients with cancer.
abstract: Tumor cells transfected to express immunostimulatory cytokines, or admixed with similarly modified bystander cells, are able to induce immune responses against unmodified tumor cells in animal models. For treatment of human patients, a vaccine composed of autologous tumor cells and IL-2-secreting allogeneic fibroblasts was developed. Autologous tumor cells were isolated from biopsy specimens. A clone (KMST 6.14) of an immortalized human fibroblast line that stably secreted 5290 IU IL-2 per 10(6) cells and per 24 hr was obtained by cationic lipofection with an expression construct for human IL-2 and Neo(r). Fifteen patients with refractory malignant tumors received 3-4 injections of irradiated KMST6.14 and autologous tumor cells in a phase-I clinical trial. Increasing transient inflammatory responses without systemic toxicity developed at vaccination sites and after injections with irradiated tumor cells only (p < 0.05). These sites contained a dense infiltrate of CD3+ T cells with numbers of CD4+ helper cells exceeding those of CD8+ cytotoxic T cells (CTL). CD8+ T-cell lines isolated from vaccination sites of 2 malignant melanoma patients but not of renal-cell carcinoma patients exhibited a dominant lytic activity against autologous tumor cells in vitro. CD8+ T-cell clones established from the vaccination site of 1 of 2 renal-cell carcinoma patients preferentially lysed autologous and partially matched allogeneic renal-cell carcinoma cells. In conclusion, a vaccine composed of IL-2 gene-transfected allogeneic fibroblasts and autologous tumor cells is able to enhance specific anti-tumor T-cell responses in vivo without major side-effects. Malignant melanoma and renal-cell carcinoma appear to be promising entities for testing of similar approaches in future therapeutic trials.
authors.affiliation: Department of Hematology/Oncology, Freiburg University Medical Center, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Veelken
authors.forename: A
authors.initials: A
authors.lastname: Mackensen
authors.forename: M
authors.initials: M
authors.lastname: Lahn
authors.forename: G
authors.initials: G
authors.lastname: Köhler
authors.forename: D
authors.initials: D
authors.lastname: Becker
authors.forename: B
authors.initials: B
authors.lastname: Franke
authors.forename: U
authors.initials: U
authors.lastname: Brennscheidt
authors.forename: P
authors.initials: P
authors.lastname: Kulmburg
authors.forename: F M
authors.initials: FM
authors.lastname: Rosenthal
authors.forename: H
authors.initials: H
authors.lastname: Keller
authors.forename: J
authors.initials: J
authors.lastname: Hasse
authors.forename: W
authors.initials: W
authors.lastname: Schultze-Seemann
authors.forename: E H
authors.initials: EH
authors.lastname: Farthmann
authors.forename: R
authors.initials: R
authors.lastname: Mertelsmann
authors.forename: A
authors.initials: A
authors.lastname: Lindemann
mesh_terms: D000328:Adult; D000368:Aged; D019496:Cancer Vaccines / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D002469:Cell Separation; D018450:Disease Progression; D005240:Feasibility Studies; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics* / Q000627:therapeutic use*; D016246:Lymphocytes, Tumor-Infiltrating / Q000166:cytology / Q000276:immunology; D008875:Middle Aged; D009369:Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D010641:Phenotype; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014611:Vaccination / Q000009:adverse effects / Q000379:methods
chemical_list: D019496:Cancer Vaccines; D007376:Interleukin-2