title: Treatment of cancer patients with ex vivo anti-CD3-activated killer cells and interleukin-2.
abstract: OBJECTIVE
  This study describes the physiologic and biologic effects resulting from the adoptive transfer of ex vivo anti-CD3-stimulated T-killer cells (T-AK) to patients with advanced cancer in combination with interleukin-2 (IL-2).
  
  
  METHODS
  Autologous peripheral-blood mononuclear cells were obtained by leukapheresis and stimulated ex vivo with anti-CD3. The stimulated cells were reinfused at one of three dose levels on the next day (5 x 10(9), 7.5 x 10(9), and 1 x 10(10)). Cell administration was followed by IL-2 given by bolus and continuous infusion (1.5 x 10(6) U/m2 and 3.0 x 10(6) U/m2, respectively) for 7 days, or continuous infusion alone (3.0 x 10(6) U/m2) for 14 days.
  
  
  RESULTS
  Pronounced leukocytosis and atypical lymphocytosis were observed with individual values as high as 80,000 and 50,000 cells/microL, respectively. The other major clinical sequelae included a marked lactic acidosis with bicarbonate levels as low as 4.0 mmol/L in some patients, and prolongation of the prothrombin time (PT) and partial thromboplastin time (PTT) due to decreases in clotting factors VII, IX, and X. Antithrombin III levels were also reduced. Hypotension associated with increased serum nitrate and neopterin levels was observed. These toxicities were accompanied by increases in hepatocellular enzymes and creatinine previously described with IL-2. These events occurred at a time when the number of circulating T-AK cells reached their peak. The amount of bolus IL-2 correlated with increases in WBC count (P = .0311), atypical lymphocytes (P = .0241), PT (P = .0006), and PTT (P = .0122).
  
  
  CONCLUSIONS
  Substantial in vivo expansion of activated T lymphocytes was induced by a protocol combining ex vivo activation of peripheral-blood cells with anti-CD3 antibody followed by adoptive transfer and IL-2 administration. The synchronous expansion of these T cells superimposed on diminished liver and kidney function from IL-2 can cause profound but reversible metabolic changes.
authors.affiliation: Biological Response Modifiers Program, Program Resources, Inc/DynCorp., Frederick, MD.
authors.forename: B D
authors.initials: BD
authors.lastname: Curti
authors.forename: D L
authors.initials: DL
authors.lastname: Longo
authors.forename: A C
authors.initials: AC
authors.lastname: Ochoa
authors.forename: K C
authors.initials: KC
authors.lastname: Conlon
authors.forename: J W
authors.initials: JW
authors.lastname: Smith
authors.forename: W G
authors.initials: WG
authors.lastname: Alvord
authors.forename: S P
authors.initials: SP
authors.lastname: Creekmore
authors.forename: R G
authors.initials: RG
authors.lastname: Fenton
authors.forename: B L
authors.initials: BL
authors.lastname: Gause
authors.forename: J
authors.initials: J
authors.lastname: Holmlund
mesh_terms: D000138:Acidosis / Q000209:etiology; D000293:Adolescent; D000328:Adult; D000368:Aged; D001778:Blood Coagulation Disorders / Q000209:etiology; D017252:CD3 Complex / Q000276:immunology*; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000009:adverse effects; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000009:adverse effects; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D007958:Leukocyte Count; D016131:Lymphocyte Subsets; D016246:Lymphocytes, Tumor-Infiltrating; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000276:immunology / Q000628:therapy*; D009566:Nitrates / Q000097:blood
chemical_list: D017252:CD3 Complex; D007376:Interleukin-2; D009566:Nitrates