Introduction mRNA electroporated autologous dendritic cells (DC) are being developed as therapeutic cancer vaccines. Potential advantages include the presentation of all potential tumor antigen confined epitopes by the patient's own HLA-molecules and the possibility for co-electroporation of RNA that improves the immunostimulatory capacity of the DC-vaccine.
Methods Immature DCs (derived from PBMC obtained by leucapheresis and cultured for 6 days in IL-4/GM-CSF supplemented medium) were electroporated with synthetic mRNA encoding a fusion protein between MAGE-A1, MAGE-A3, MAGE-C2, Tyrosinase, MelanA/MART-1 or gp100, and DC-LAMP. DC were co-electroporated for the purpose of maturation with either poly I:poly C12U or mRNA encoding a constitutive activated TLR-4 receptor, CD70 and CD40-ligand). DC (12.5 106/antigen) were administered by 4 to 6 ID-injections q2w, and q8w thereafter. Interferon alfa-2b (IFN-a2b, 5 MIU TIW) was initiated at progression (cohort 1), concomitant (cohorts 2 and 3) or following the 4th vaccine (cohort 4).
Results A total of 70 melanoma pts were recruited. Baseline characteristics: 44M/26F; med age: 46 y (range 27–75); AJCC stage III: 30, IV-M1a: 8, -M1b: 6, -M1c: 26; WHO-PS 0: 46, 1: 19, 2: 5; serum LDH nl.: 59, -elevated: 13; primary of the H/N: 11, trunk/limbs: 48, acral: 5, unknown: 6; ulcerated primary: 12, -not ulcerated: 13, -unknown: 45. A total of 466 DC-vaccines were administered (median/pt: 6, range 2–18). Vaccine related AE's: gr2 local injection site reactions: all pts; gr2 fever/lethargy: 3 pt; gr3 constitutional IFN-a2b side effects: 5 pt; skin depigmentation: 11 pt. Fifteen out of 30 pts without evaluable disease (ED) at baseline have relapsed, 3 have died (median RFS & OS not reached). The tumor response among 40 pts with ED at baseline: 14 SD (36%) according to RECIST; 2 CR, 2 PR and 14 SD (DCR 48%) according to immune related response criteria (irRC). The mOS for ED pts is 13 mths (95% CI 11–15). Baseline LDH was the only independent prognostic baseline covariable (P<0.001), and disease control by irRC was the strongest surrogate marker for OS (P<0.001). DCR by irRC retained its significance as an independent prognostic surrogate marker for TTP and OS when analyzed by Cox multivariate logistic regression (P<0.01).
Conclusion Therapeutic vaccination with autologous mRNA electroporated DC combined with IFN-a2b is feasible, safe, and has anti-tumor activity in a subset of patients with advanced melanoma. A significant correlation between activity by irRC and survival was identified. Stratification by baseline LDH and the use of irRC is indicated in future studies with mRNA electroporated DC-vaccines.