title: Clinical observations on adoptive immunotherapy with vaccine-primed T-lymphocytes secondarily sensitized to tumor in vitro.
abstract: The adoptive immunotherapy of human malignancy requires reliable methods to sensitize and expand patients' T-cells reactive to autologous tumors. In animal studies, we have generated therapeutic effector cells against a poorly immunogenic tumor by a two-step procedure: vaccination of the host followed by the secondary stimulation of vaccine-primed lymph node (LN) cells by in vitro sensitization (IVS) with tumor in the presence of interleukin 2 (IL-2). Based on these observations, we performed a clinical trial in patients with advanced cancer to evaluate the antitumor efficacy of vaccine-primed LN cells which were similarly activated in vitro. Patients were vaccinated with irradiated autologous tumor admixed with Bacillus Calmette-Guérin and had draining LN excised 10 days later for IVS culture. During IVS culture, LN cells expanded up to 14-fold (average of 8.4-fold). A mean of 6.7 x 10(9) cells was infused in ten patients (seven melanoma, three renal cell cancer) along with the concomitant i.v. administration of IL-2 (180,000 IU/kg every 8 h for 5 days). Phenotype analysis of IVS-LN cells revealed 78 +/- 4% CD3+ T-cells which were predominantly CD4+ (67 +/- 5%) with expression of HLA-DR and IL-2 receptor. IVS-LN cells displayed relative specificity of autologous tumor lysis in four of ten cases compared to zero of seven IVS-peripheral blood lymphocytes derived from the same patients as measured by the 51Cr release assay. One mo after therapy, seven of nine patients treated with IVS-LN cells and IL-2 developed delayed-type hypersensitivity reactivity to autologous tumor compared to zero of nine patients treated with tumor vaccination and IL-2 only (P < 0.002). These observations suggest that antitumor reactivity was passively transferred with the IVS-LN cells. Major toxic side effects including fever, hepatic dysfunction, and weight gain associated with the capillary leak syndrome were associated with exogenous IL-2 administration. Tumor vaccination and cell transfer were well tolerated without significant complications. Of the ten patients treated with IVS-LN cells and IL-2, there were one partial and one minor response, and one patient has had stable disease for 27+ mo. There was no evidence of tumor response in ten patients treated with tumor vaccination and IL-2 only. Further clinical studies evaluating the antitumor reactivity of vaccine-primed LN cells are warranted.
authors.affiliation: Department of Surgery, University of Michigan Medical Center, Ann Arbor 48109.
authors.forename: A E
authors.initials: AE
authors.lastname: Chang
authors.forename: H
authors.initials: H
authors.lastname: Yoshizawa
authors.forename: K
authors.initials: K
authors.lastname: Sakai
authors.forename: M J
authors.initials: MJ
authors.lastname: Cameron
authors.forename: V K
authors.initials: VK
authors.lastname: Sondak
authors.forename: S
authors.initials: S
authors.lastname: Shu
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000628:therapy; D003602:Cytotoxicity, Immunologic; D005260:Female; D006801:Humans; D006968:Hypersensitivity, Delayed; D016219:Immunotherapy, Adoptive / Q000009:adverse effects; D007376:Interleukin-2 / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000276:immunology / Q000628:therapy; D008198:Lymph Nodes / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000628:therapy; D008875:Middle Aged; D009369:Neoplasms / Q000628:therapy*; D010641:Phenotype; D013601:T-Lymphocytes / Q000276:immunology*; D014611:Vaccination; D014612:Vaccines / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D017252:CD3 Complex; D007376:Interleukin-2; D014612:Vaccines