CLINICAL AND IMMUNOLOGICAL CHANGES IN AIDS PATIENTS FOLLOWING ADOPTIVE THERAPY WITH ACTIVATED AUTOLOGOUS CD8 T-CELLS AND INTERLEUKIN-2 INFUSION

Objectives: (1) To determine the safety and feasibility of repetitive reinfusions of activated autologous CD8 cells followed by low-dose con tinuous interleukin (IL)-2 infusion in patients with AIDS. (2) To stud y the relationships between clinical responses, surface marker phenoty pic distributions and cytokine expression patterns of both cultured CD 8 cells and lymphocytes in the peripheral blood compartment. Design: S ix adult patients with Centers for Disease Control and Prevention grou p IV HIV-1 disease ranging from mild to severe, were studied. All pati ents were receiving zidovudine prior to and during the study period, a nd had initial CD4 and CD8 cell counts > 50 and 200 x 10(6)/l, respect ively. Methods: Autologous CD8 T cells (10(8)-10(10)) were reinfused f ive times after ex vivo culture and stimulation with phytohemagglutini n and recombinant (r) IL-2. The fifth such infusion was followed by 5 days of rlL-2 infusion. Phenotypes and cytokine expression patterns of the expanded cells were determined as well as serum levels of immune mediators throughout the study. Results: Patients showed stable CD4 an d CD8 cell counts, p24 antigenemia, and minimal toxicity over the 24-w eek protocol study. Clinical improvement was observed in lymphadenopat hy (six out of six), oral hairy leukoplakia (three out of four), and K aposi's sarcoma (KS; two out of two) in the patients studied. In vivo induction of detectable levels of bioactive acid-stable interferon (IF N)-alpha, but not of other cytokines studied, upon activated CD8 cell reinfusion was associated consistently with improvement of oral hairy leukoplakia. However, partial regression of KS was observed after the CD8 cell infusion cycles and without IFN-alpha induction. In one of th e two patients studied, KS regression was associated with decreased IL -1 alpha serum levels. In the other patient, who had failed previous I FN-alpha therapy, KS regression was observed after a decline in reinfu sed CD8 cell-associated gene expression of tumor necrosis factor (TNF) -beta. Both IL-1 alpha and TNF-beta are growth factors for KS cells. C onclusions: These observations demonstrate the feasibility and safety of ex vivo CD8 cell activation, expansion, and reinfusion, and rlL-2 i nfusion in AIDS patients. The findings in this Phase I trial suggest p otential clinical efficacy and encourage Phase II trials. The correlat ions obtained between clinical and immunological states could contribu te to an understanding of the relationship between CD8 T-cell function and HIV-1-associated disease progression.