title: Adoptive cellular therapy with tumor vaccine draining lymph node lymphocytes after vaccination with HLA-B7/beta2-microglobulin gene-modified autologous tumor cells.
abstract: Adoptive immunotherapy with anti-CD3-expanded lymphocytes from lymph nodes draining alloantigen gene-modified autologous tumor vaccines is an effective treatment of poorly immunogenic murine tumors. This phase I/II study was performed to determine the feasibility and toxicity of combining ex vivo gene transfer of autologous tumor cells and adoptive immunotherapy with anti-CD3-expanded tumor vaccine draining lymph node lymphocytes (TVDLN) in patients with metastatic melanoma and renal cell cancer (RCC). To facilitate the generation of tumor-specific lymphocytes in the TVDLN, autologous tumor cells were modified by gene transfer ex vivo to express the alloantigen HLA-B7, a modification that has the potential to enhance the immunogenicity of the tumor cells. After vaccination with gene-modified tumor cells, patients' lymph nodes were harvested; TVDLN lymphocytes were activated and expanded ex vivo with anti-CD3 and interleukin-2 (IL-2), and adoptively transferred to patients in combination with systemic IL-2. Twenty patients, nine with melanoma and 11 with RCC were treated. Tumor was harvested successfully in all 20 patients. Ex vivo gene transfer was performed using lipofection with a lipid: DNA plasmid complex containing the genes for HLA-B7 and beta2-microglobulin. The mean expression of HLA-B7 by autologous tumor cells after gene transfer was 4.53% (range 0.3%-12.1%). Lymph nodes were harvested from all 20 patients with a mean of 53 x 107 and 60 x 107 cells obtained from the gene-modified and unmodified tumor vaccine sites, respectively. Successful expansion of adequate TVDLN was accomplished in 19 of 20 harvests of unmodified vaccines and in 18 of 20 gene-modified vaccines. No major toxicities were noted after vaccination with autologous tumor cells or adoptive transfer of ex vivo activated TVDLN lymphocytes. Typical IL-2-related toxicities were observed in all patients. No objective tumor regressions were observed. MHC class I restricted, tumor-specific cytokine secretion was observed in lymphocytes from TVDLN and the peripheral blood of vaccinated patients.
authors.affiliation: Laboratory of Molecular and Tumor Immunology, Earle A. Chiles Research Institute, Providence Portland Medical Center, Oregon 09713, USA.
authors.forename: Sybren L
authors.initials: SL
authors.lastname: Meijer
authors.forename: Annemieke
authors.initials: A
authors.lastname: Dols
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Urba
authors.forename: Hong-Ming
authors.initials: HM
authors.lastname: Hu
authors.forename: John W
authors.initials: JW
authors.lastname: Smith II
authors.forename: John
authors.initials: J
authors.lastname: Vetto
authors.forename: William
authors.initials: W
authors.lastname: Wood
authors.forename: Teri
authors.initials: T
authors.lastname: Doran
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Chu
authors.forename: Philip
authors.initials: P
authors.lastname: Sayaharuban
authors.forename: W Gregory
authors.initials: WG
authors.lastname: Alvord
authors.forename: Bernard A
authors.initials: BA
authors.lastname: Fox
mesh_terms: D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology*; D002292:Carcinoma, Renal Cell / Q000276:immunology* / Q000628:therapy; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D018014:Gene Transfer Techniques; D015793:HLA-B7 Antigen / Q000235:genetics* / Q000276:immunology; D006801:Humans; D006968:Hypersensitivity, Delayed; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007376:Interleukin-2 / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000276:immunology* / Q000628:therapy; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000628:therapy; D008875:Middle Aged; D014611:Vaccination; D001613:beta 2-Microglobulin / Q000235:genetics* / Q000276:immunology
chemical_list: D019496:Cancer Vaccines; D016207:Cytokines; D015793:HLA-B7 Antigen; D007376:Interleukin-2; D001613:beta 2-Microglobulin