title: Adoptive immunotherapy with vaccine-primed lymph node cells secondarily activated with anti-CD3 and interleukin-2.
abstract: OBJECTIVE
  In preclinical studies, we have reported the ability to induce immune T cells in lymph nodes (LN) primed by in vivo vaccination with tumor cells admixed with a bacterial adjuvant. These LN cells can be activated and expanded ex vivo for the successful immunotherapy of established tumors. We have applied these methods to generate vaccine-primed LN in patients with advanced melanoma and renal cell cancer (RCC) for therapy.
  
  
  METHODS
  Irradiated autologous tumor cells admixed with bacille Calmette-Guérin (BCG) were used to vaccinate patients. Seven days later, draining LN were removed for activation with anti-CD3 monoclonal antibody (mAb) followed by expansion in interleukin-2 (IL-2). Activated LN cells were administered intravenously (IV) with the concomitant administration of IL-2.
  
  
  RESULTS
  A total of 23 patients were evaluated (11 melanoma and 12 RCC). Vaccine-primed LN were expanded ex vivo with a mean of 8.4 x 10(10) cells administered per patient. Among 20 patients assessed, 15 demonstrated minimal cytotoxicity of autologous tumor cells by the activated LN cells, with the remaining mediating nonspecific cytotoxicity. By contrast, a majority of the activated LN cells showed highly specific release of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon gamma (IFN-gamma) to autologous but not allogeneic tumor stimulation. This tumor-specific cytokine release was found to be major histocompatibility complex (MHC) class I-restricted, which indicates the involvement of CD8+ cells. Among 11 melanoma patients, one had a partial tumor response. Among 12 RCC patients, two had complete and two partial responses. A trend (P = .066) between the enhancement of delayed-type hypersensitivity (DTH) reactivity to autologous tumor after therapy and tumor regression was observed.
  
  
  CONCLUSIONS
  Tumor vaccines can be used to induce immunologically specific T-cell responses against melanoma and RCC in draining LN. Anti-CD3/IL-2 activation of primed LN cells can be reliably performed for clinical therapy and appears to have activity in patients with metastatic RCC.
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, USA. aechang@umich.edu
authors.forename: A E
authors.initials: AE
authors.lastname: Chang
authors.forename: A
authors.initials: A
authors.lastname: Aruga
authors.forename: M J
authors.initials: MJ
authors.lastname: Cameron
authors.forename: V K
authors.initials: VK
authors.lastname: Sondak
authors.forename: D P
authors.initials: DP
authors.lastname: Normolle
authors.forename: B A
authors.initials: BA
authors.lastname: Fox
authors.forename: S
authors.initials: S
authors.lastname: Shu
mesh_terms: D000328:Adult; D001500:BCG Vaccine / Q000627:therapeutic use*; D017252:CD3 Complex / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000628:therapy*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D006801:Humans; D006968:Hypersensitivity, Delayed; D007111:Immunity, Cellular / Q000187:drug effects; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000276:immunology / Q000628:therapy*; D015979:Killer Cells, Lymphokine-Activated / Q000187:drug effects*; D008213:Lymphocyte Activation / Q000187:drug effects*; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects*; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D008875:Middle Aged; D010641:Phenotype; D016896:Treatment Outcome
chemical_list: D001500:BCG Vaccine; D017252:CD3 Complex; D007376:Interleukin-2; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor