Immature DCs were generated by culturing monocytes in the presence of 1% autologous plasma, granulocyte- macrophage colony-stimulating factor (GMC-SF), and IL-4. After leukapheresis, monocytes were enriched by plastic adherence. On day 6, DCs were harvested and co- electroporated with TriMix-mRNA (CD40L-, CD70-, and caTLR4-encoding mRNA) and mRNA encoding one of four melanoma-associated antigens (MAGE-A3, MAGE-C2, tyrosinase, or
gp100) linked to an HLA class II targeting signal. After electroporation, the four different TriMixDC-MEL cellular constituents were mixed at equal ratios and cryopreserved. DCs were thawed 2 to 3 hours before injection.
Eligible patients received ipilimumab intravenously (IV) at a dose of 10 mg/kg over a period of 90 minutes once every 3 weeks for four doses. One hour after the end of the ipilimumab administration, TriMixDC- MEL was administered intravenously (20×106 DCs) and intradermally (4×10 DCs). In the first 18 patients, one TriMixDC-MEL administration was performed 2 weeks before combined administration with
Grade 2 TriMixDC-MEL dermal injection site reactions were observed in all patients. Chills (grade 1 to 2) occurring within the first hour after intravenous infusion of TriMixDC-MEL occurred in 38% of patients, and mild flu-like symptoms (within the first 72 hours after infusion) occurred in 85% of patients. A total of 14 patients (36%) developed treatment-related grade 3 or 4 AEs. Allimmune-related AEs were managed using established treatment algorithms. Grade 1 to 2 dermatitis (diffuse itching, erythema) was the most frequent AE and was reported by 64% of patients. Systemic corticosteroids were required to manage immune- related AEs in 18 patients (46%). No treatment-related deaths occurred. Treatment-related AEs were completely reversible in all patients except for hypopituitarism requiring continued hormonal substitution in all affected patients.
Tumor Response and Duration of Response
The investigator-assessed best ORR by irRC was 38%, including eight patients (20%) with a complete response (CR) and seven patients (18%) with a partial response (PR). Seven of the eight complete responses and one of the seven partial responses were ongoing at the time of this analysis. Median follow-up time for patients with an ongoing response is 36 months (range, 22 to 43 months). Tumor responses occurred by an atypical pattern in four patients (10%). An additional six patients (15%) experienced stable disease that persisted for a median of 9.5 months (range, 5 to 20 months).
Over-all Survival and Progression-fee Survival
The disease control rate (DCR) at 6 months was 51% (95% CI, 36% to 67%). At the time of data analysis, a total of 31 patients (79%) had been diagnosed with progression of disease. The estimated median PFS was 27 weeks (95% CI, 9 to 44 weeks). The 1-year, 2-year, and 3-year PFS rates were 33% (95% CI, 18% to 48%), 22% (95% CI, 9% to 36%), and 18% (95% CI, 5% to 31%), respectively. The median follow-up time for the 14 surviving patients was 157 weeks (range, 72 to 185 weeks). The estimated median OS was 59 weeks (95% CI, 40 to 79 weeks). The 1-year, 2-year, and 3-year OS rates were 59% (95% CI, 43% to 74%), 38% (95% CI, 23% to 53%), and 34% (95% CI, 19% to 50%), respectively.
The combination of TriMixDC-MEL and ipilimumab is tolerable and results in an encouraging rate of highly durable tumor responses in patients with pretreated advanced melanoma.