Adoptive transfer of ex vivo activated memory T-cells with or without cyclophosphamide for advanced metastatic melanoma: Results in 36 patients

Abstract

Autolymphocyte therapy (ALT) is the infusion of autologous peripheral blood mononuclear cells (PBMC) activated ex vivo by a cytokine-rich supernatant (T3CS) generated from a previous autologous lymphocyte culture 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 exogenous 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. However, 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 cyclophosphamide (CY) (10 patients). Over this time period, the cell activation method evolved from using cytokine supernatants derived from a one-way allogeneic mixed lymphocyte culture (MLCS), to the current practice of utilising anti-CD3 and autologous cytokines (T3CS). There were 21 men and 15 women, average age 57 years, range 30-82. 27 had failed prior therapies and 9 had no prior therapy. A total of 161 infusion of ALT cells 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 grades 1 and 2 reactions to ALT-cell infusions. Transient cytopenias were seen in patients receiving CY. Sixty-one per cent (22/36) of patients received the planned six ALT-cell infusions, while 39% did not due to progressive disease. In 33 evaluable patients, there were four complete responses, four partial responses and 6 patients with stable disease (SD). Responding patients and those with SD had prolonged survival compared to historical controls when matched for number of organ systems involved. Ex vivo depletion of CD45RO+ T-cells revealed preferential lysis of autologous and HLA-A-matched melanoma targets that was dependent on these memory T-cells. These data suggest that adoptive cellular therapy using ex vivo activated memory T-cells with and without CY is active, has low toxicity, is tumour-specific and can result in clinical benefit in patients with disseminated melanoma.