title: Pilot clinical trial of type 1 dendritic cells loaded with autologous tumor lysates combined with GM-CSF, pegylated IFN, and cyclophosphamide for metastatic cancer patients.
abstract: Twenty-four patients with metastatic cancer received two cycles of four daily immunizations with monocyte-derived dendritic cells (DC). DC were incubated with preheated autologous tumor lysate and subsequently with IFN-α, TNF-α, and polyinosinic:polycytidylic acid to attain type 1 maturation. One DC dose was delivered intranodally, under ultrasound control, and the rest intradermally in the opposite thigh. Cyclophosphamide (day -7), GM-CSF (days 1-4), and pegIFN alpha-2a (days 1 and 8) completed each treatment cycle. Pretreatment with cyclophosphamide decreased regulatory T cells to levels observed in healthy subjects both in terms of percentage and in absolute counts in peripheral blood. Treatment induced sustained elevations of IL-12 in serum that correlated with the output of IL-12p70 from cultured DC from each individual. NK activity in peripheral blood was increased and also correlated with the serum concentration of IL-12p70 in each patient. Circulating endothelial cells decreased in 17 of 18 patients, and circulating tumor cells markedly dropped in 6 of 19 cases. IFN-γ-ELISPOT responses to DC plus tumor lysate were observed in 4 of 11 evaluated cases. Tracing DC migration with [(111)In] scintigraphy showed that intranodal injections reached deeper lymphatic chains in 61% of patients, whereas with intradermal injections a small fraction of injected DC was almost constantly shown to reach draining inguinal lymph nodes. Five patients experienced disease stabilization, but no objective responses were documented. This combinatorial immunotherapy strategy is safe and feasible, and its immunobiological effects suggest potential activity in patients with minimal residual disease. A randomized trial exploring this hypothesis is currently ongoing.
authors: Gene Therapy and Hepatology Unit, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain.
authors: Carlos
authors: C
authors: Alfaro
authors: Jose L
authors: JL
authors: Perez-Gracia
authors: Natalia
authors: N
authors: Suarez
authors: Javier
authors: J
authors: Rodriguez
authors: Miguel
authors: M
authors: Fernandez de Sanmamed
authors: Bruno
authors: B
authors: Sangro
authors: Salvador
authors: S
authors: Martin-Algarra
authors: Alfonso
authors: A
authors: Calvo
authors: Miriam
authors: M
authors: Redrado
authors: Alice
authors: A
authors: Agliano
authors: Alvaro
authors: A
authors: Gonzalez
authors: Inmaculada
authors: I
authors: Rodriguez
authors: Elixabet
authors: E
authors: Bolaños
authors: Sandra
authors: S
authors: Hervás-Stubbs
authors: Javier
authors: J
authors: Perez-Calvo
authors: Alberto
authors: A
authors: Benito
authors: Ivan
authors: I
authors: Peñuelas
authors: Carmen
authors: C
authors: Vigil
authors: José
authors: J
authors: Richter
authors: Ivan
authors: I
authors: Martinez-Forero
authors: Ignacio
authors: I
authors: Melero
mesh_terms: D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000276:immunology*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use; D002469:Cell Separation; D003520:Cyclophosphamide / Q000627:therapeutic use; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D016898:Interferon-alpha / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D010865:Pilot Projects; D011092:Polyethylene Glycols / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000627:therapeutic use; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide; C100416:peginterferon alfa-2a