Therapeutic vaccination with an autologous TriMix-Dendritic cell vaccine combined with sequential interferon alfa-2b in ........

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Author(s): S. Wilgenhof,
A. M. Van Nuffel, D. Benteyn, L. Pierret, C. Heirman, A. De Coninck, I.
Van Riet, A. Bonehill, K. Thielemans, B. Neyns; Vrije Universiteit
Brussel, Brussels, Belgium; UZ Brussel, Brussels, Belgium
 
Abstract:
Background:
Electroporation of dendritic cells (DC) with mRNA encoding
fusion-proteins of a HLA-class II targeting signal and a melanoma
associated antigen (MAA) together with mRNA encoding CD40 ligand, a
constitutively active TLR4 and CD70 (TriMix) improves the
immunostimulatory capacity of autologous DC.
 
Methods: Following
leukapheresis, immature DCs (derived from adherent PBMC cultured for 6
days in IL-4 / GM-CSF supplemented medium) are electroporated with mRNA
encoding MAGE-A3, MAGE-C2, Tyrosinase and gp100 linked to DC-LAMP, and
TriMix mRNA. TriMix-DC (12.5 106/antigen) are cryopreserved and administered by 4 ID-injections q2w, and q8w thereafter. After the 4th
vaccination, interferon alfa-2b (IFN- a2b, 5 MIU TIW) is initiated.
Immune monitoring is performed by skin biopsy of a vaccine injection
site. Biopsies are investigated by IHC and by analyzing the activation
(CD137+), cytolytic capacity (CD107a+), and cytokine release (IFN-? and
TNF-?) of DTH infiltrating T-cells in response to autologous EBV-B
cells expressing MAA.
 
Results: 29 pts (17M/12F; med age 49,
range 28-75) with stage III/IV melanoma, nl LDH, and no CNS metastases
were recruited. Vaccine related AE's (first 24 pts): gr2 local
injection site reactions (all pts); fever & lethargy (gr2, 1 pt).
Pts (20) who initiated IFN-a2b experienced constitutional side effects
(gr3, 1 pt). Vaccine-specific DTH infiltrating T cells were documented
post-vaccination in 13/17 pts (10/13 pts had a CD137+CD8+ and 2/13 pts
a CD4+ response). Out of the 11 pts without evaluable disease, 2 had a
local recurrence (salvaged by surgery). After a mFU of 7.8 mths (range
4.3-13.7) all pts remain disease-free. Out of the 13 pts with
measurable disease, BOR (RECIST) was 8 SD and 5 PD; 1 pt with initial
PD subsequently obtained a PR. Regression of metastases occurred in
lung- (2 pts), orbita- (1 pt) and lymph node metastases (3 pts). After
a mFU of 7 mths (range 1-14), the mPFS is 3,1 mths (95% CI 2,29-4,08);
4 pts remain progression-free after respectively 5, 8, 10 and 11 mths
of follow-up.
 
Conclusions: Therapeutic vaccination with
TriMix-DC combined with sequential IFN-a2b is feasible, safe,
immunogenic and associated with anti-tumor activity in patients with
advanced melanoma.