ADOPTIVE TRANSFER OF EX-VIVO ACTIVATED MEMORY T-CELLS WITH OR WITHOUTCYCLOPHOSPHAMIDE FOR ADVANCED METASTATIC MELANOMA - RESULTS IN 36 PATIENTS

Autolymphocyte therapy (ALT) is the infusion of autologous peripheral blood mononuclear cells (PBMC) activated ex vivo by a cytokine-rich su pernatant (T3CS) generated from a previous autologous lymphocyte cultu re using low doses of the anti-CD3 mitogenic monoclonal antibody. The mechanism of action is enhancement of a recall response by CD45RO(+) ( memory) T-cells (ALT cells) to host tumour without dependence on exoge nous interleukin (IL)-2. The existence of anti-tumour-specific T-cells in melanoma patients has been well described, and efforts to utilise them therapeutically have achieved modest tumour response rates. Howev er, few long-term survival data have been reported. From 1986 to 1992, we treated 36 patients with disseminated melanoma using ALT alone (26 patients) or adoptive chemoimmunotherapy using ALT and cyclophosphami de (CY) (10 patients). Over this time period, the cell activation meth od evolved from using cytokine supernatants derived from a one-way all ogeneic mixed lymphocyte culture (MLCS), to the current practice of ut ilising anti-CD3 and autologous cytokines (T3CS). There were 21 men an d 15 women, average age 57 years, range 30-82. 27 had failed prior the rapies and 9 had no prior therapy. A total of 161 infusion of ALT cell s were given: 65 with cells activated in MLCS and 96 with T3CS. There were no grade 3 adverse events, and an approximate 20% incidence of gr ades 1 and 2 reactions to ALT-cell infusions. Transient cytopenias wer e seen in patients receiving CY. Sixty-one per cent (22/36) of patient s received the planned six ALT-cell infusions, while 39% did not due t o progressive disease. In 33 evaluable patients, there were four compl ete responses, four partial responses and 6 patients with stable disea se (SD). Responding patients and those with SD had prolonged survival compared to historical controls when matched for number of organ syste ms involved. Ex vivo depletion of CD45RO(+) T-cells revealed preferent ial lysis of autologous and HLA-A-matched melanoma targets that was de pendent on these memory T-cells. These data suggest that adoptive cell ular therapy using ex vivo activated memory T-cells with and without C Y is active, has low toxicity, is tumour-specific and can result in cl inical benefit in patients with disseminated melanoma.