Vaccination of melanoma patients using dendritic cells loaded with an allogeneic tumor cell lysate.

The aim of the present phase I/II study was to evaluate the safety, immune responses and clinical activity of a vaccine based on autologous dendritic cells (DC) loaded with an allogeneic tumor cell lysate in advanced melanoma patients. DC derived from monocytes were generated in serum-free medium containing GM-CSF and IL-13 according to Good Manufacturing Practices. Fifteen patients with metastatic melanoma (stage III or IV) received four subcutaneous, intradermal, and intranodal vaccinations of both DC loaded with tumor cell lysate and DC loaded with hepatitis B surface protein (HBs) and/or tetanus toxoid (TT). No grade 3 or 4 adverse events related to the vaccination were observed. Enhanced immunity to the allogeneic tumor cell lysate and to TAA-derived peptides were documented, as well as immune responses to HBs/TT antigens. Four out of nine patients who received the full treatment survived for more than 20 months. Two patients showed signs of clinical response and received 3 additional doses of vaccine: one patient showed regression of in-transit metastases leading to complete remission. Eighteen months later, the patient was still free of disease. The second patient experienced stabilization of lung metastases for approximately 10 months. Overall, our results show that vaccination with DC loaded with an allogeneic melanoma cell lysate was feasible in large-scale and well-tolerated in this group of advanced melanoma patients. Immune responses to tumor-related antigens documented in some treated patients support further investigations to optimize the vaccine formulation.

Anti-tumor properties of human-activated macrophages produced in large scale for clinical application.

When properly activated, macrophages can be tumoricidal. To harness the therapeutic potential of these cells, we have developed a process for ex vivo production of large numbers of IFN-gamma-activated monocyte-derived macrophages. These monocyte-derived activated killer (MAK) cells have been safely administered to cancer patients with minimal residual disease in phase I/II clinical studies. To evaluate efficacy of treatment with MAK cells, phase III clinical studies are necessary. The process of MAK cell production has been further optimized and qualified for use in large cohorts of patients. In this study, we characterized MAK cells produced in large scale by studying their phenotype and functions. MAK cells were shown to exert anti-tumor activity by killing tumor cells and inhibiting their proliferation. These activities were enhanced by activation with IFN-gamma and addition of anti-tumor antibodies. Tumor necrosis factor-alpha (TNF-alpha) was one of the mediators used by MAK cells to inhibit tumor proliferation. To facilitate logistics of clinical trials, a process for MAK cell cryopreservation has been developed. We verified in vitro that cryopreserved cells retained the activity of fresh cells and were stable during storage. The safety and efficacy of cryopreserved MAK cells (Bexidem) are currently being assessed on superficial bladder cancer patients in a phase II/III clinical trial.