Clinical and Immunological Response Following hTERT/Survivin mRNA-Loaded Dendritic Cell Vaccination Combined With Ex-Vivo Expanded T Cell Transfer In Melanoma Patients
Authors: Kvalheim Gunnar , Bigalke Iris , Torhaug Siri , Lundby Marianne , Mollat Camilla , Inderberg Suso Else-Marit , Kolstad Arne , Gaudernack Gustav , Rasmussen Anne-Marie , Aamdal Steinar 
Published: October 2019

New immunotherapy strategies have recently been developed combining peptide or dendritic cell (DC) vaccination with infusion of vaccine-primed and ex vivo expanded T cells. The hypothesis is that adoptive transfer of ex vivo expanded tumor specific T cells can improve progression-free and overall survival by restoring anti-tumor immunity. In a phase I/II clinical trial on malignant melanomas stage IV patients received DC vaccination prior to transfer of ex vivo expanded T cells. Our strategy was to target hTERT and survivin since both is highly expressed in most cancers. The vaccine consisted of autologous DCs loaded with hTERT and survivin mRNA. Prior to each DC vaccination the patients received 5 days of Temozolomide treatment to reduce the number of regulatory T cells (Treg). Following 2 monthly DC vaccinations, blood samples were tested for immune response against hTERT and survivin overlapping peptides. Immune responders were offered injection of T cells. The Elutra fraction of T cells was depleted of Treg using Dynabeads CD25 prior to expansion with Dynabeads CD3/CD28 in a WAVE bioreactor. After 10 days the beads were removed and T cells were washed. 3x1010 expanded T cells were injected fresh and DC vaccination was continued. Prior to T cell infusion, the patients received non-myeloablative conditioning with Fludarabine and Cyclophosphamide
Here we present the results from three patients receiving expanded T cells. Immune response against hTERT and survivin peptides were detected in blood samples from 7 to 11 weeks of DC vaccination. After 4-7 months of DC vaccination the T cells were expanded for 10 days prior to injection. DC vaccination was continued 1 day after T cell injection. Infused T cells expanded significantly in vivo and in two of the three patients currently tested both patients showed response against hTERT and survivin peptides. Blood samples taken monthly after T cell injection demonstrated immune response against the same peptides. In one of patients the number of Treg was high (> 4%) before and during vaccination and returned to low numbers (<1%) after T cell injection. Since these findings might explain the beneficial effect of the vaccination we are currently investigating if the number of Tregs in blood show the same profile in the two other patients. Progression free survival (PFS) in the three patients was 31,20 and 11 months respectively. Patients with the shortest PFS relapsed very shortly after the T-cell infusion in spite of an objective immunresponse following the last DC vaccine. Metastatic melanoma patients included in this study given DC vaccines without T-cells had a median PFS of 7 months (3-13). We therefore conclude that dendritic cell vaccination combined with ex-vivo expanded T cell transfer can be an efficient immunotherapy strategy in melanoma patients.

Disclosures:
No relevant conflicts of interest to declare.