Abstract 2306: Treatment with hTERT/survivin mRNA-loaded dendritic cells combined with autologous ex vivo expanded T cells improves progression free survival in stage IV melanoma patients when compared to dendritic cell vaccines alone
Authors: Bigalke Iris , Aamdal Elin , Torhaug Siri , Lundby Marianne , Inderberg Else M. , Gaudernack Gustav , Rasmussen Anne M. , Aamdal Steinar , Kvalheim Gunnar 
Published: July 2016

Abstract
In previous studies with tumor specific antigen loaded dendritic cells (DCs) we have shown that 50% of patients with metastatic malignant melanoma mount specific immune responses and clinical effects. However responses were only transient.
Here we investigated, in a phase I/II study, if the combination of autologous DCs loaded with mRNA hTERT and survivin followed by transfusion of autologous ex-vivo expanded polyclonal T cells can strengthen the immune response and improve survival.
Sixteen melanoma patients with non resectable metastases were included.
Monocyte derived DCs were generated according to standard protocol using Jonuleit maturation cocktail.
Patients received 4 vaccines in weekly intervals, a DTH-challenge in week 6, followed by monthly boosts with either 5 or 10 x10E+6 DCs.
Blood samples were taken before and during DC vaccination and used for testing of specific immune responses against hTERT and survivin.
Patients with immune responses were offered additional treatment with T cells.
Fourteen patients could be evaluated, seven showing specific immune responses against hTERT and/or survivin. Three of them received a dose of 3×1010 expanded T cells after pre-treatment with Fludarabin and Cyclophosaphamide. DC vaccination was continued the day after T cell transfer.
Patient (Pt) 1 and 2 showed an increase of hTERT specific T cells in peripheral blood after T cell transfer. Pt 1 lost the hTERT specific response 20 months after beginning of DC-vaccination correlating with progression of the disease.
Pt 2 lost the hTERT response 29 months after start of DC-vaccination and proceeded with a response against surviving. Thereafter progression of disease occurred.
Pt 3 had a response against survivin prior to T cell collection and at the same time progression occurred. Following administration of expanded T-cells a strong increase of survivin specific T cells in peripheral blood was detected. In spite of this the patient only had a progression free survival of 11 months.
Patients were given the checkpoint inhibitor Ipilimumab when progressing and Pt 1 and Pt 2 are still in stable disease.
Patients who did not mount any immune response during DC therapy had a mean PFS of 4,7 (2-7) months while patients with specific immune responses show a mean PFS of 9 (6-14) months.
Retrospectively we performed an extended analysis of the DCs and their impact on immune responses. Flow-analysis showed a patient individual expression of maturation markers and co-stimulatory molecules. Mimicking T cell encounter by CD40L stimulation showed individual differences of IL-10 release but no IL-12p70.
Differences in quality of the DCs did not have an impact on immune responses.
Our data show that patients receiving expanded T cells after mounting a specific immune response have a longer PFS when compared to patients with DC vaccination alone.
Citation Format: Iris Bigalke, Elin Aamdal, Siri Torhaug, Marianne Lundby, Else M. Inderberg, Gustav Gaudernack, Anne M. Rasmussen, Steinar Aamdal, Gunnar Kvalheim. Treatment with hTERT/survivin mRNA-loaded dendritic cells combined with autologous ex vivo expanded T cells improves progression free survival in stage IV melanoma patients when compared to dendritic cell vaccines alone. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2306.