TY - JOUR
T1 - A phase I clinical trial on the combined intravenous (IV) and intradermal (ID) administration of autologous TriMix-DC cellular therapy in patients with pretreated melanoma (TriMixIDIV)
AU - Neyns, Bart
AU - Wilgenhof, Sofie
AU - Van Nuffel, Am
AU - Benteyn, Daphné
AU - Heirman, Carlo
AU - Van Riet, Ivan
AU - Bonehill, Aude
AU - Corthals, Jurgen
AU - Thielemans, Kris
PY - 2011/5
Y1 - 2011/5
N2 - Background: Autologous monocyte derived dendritic cells (DC) electroporated with synthetic messenger RNA (smRNA) encoding CD40 ligand, a constitutively active TLR4, and CD70 (TriMixDC), together with smRNA encoding fusion-proteins of a HLA-class II targeting signal and a melanoma associated antigen are immunogenic when administered ID (Wilgenhof et al. ASCO AM 2009). The TriMixIDIV clinical trial investigates the safety, immunogenicity, and activity of combined ID and IV administration in patients with pretreated melanoma. Methods: Following leukapheresis, immature DC (derived from adherent PBMC cultured for 6 days in IL-4/GM-CSF supplemented medium) are electroporated with smRNA encoding MAGE-A3, MAGE-C2, Tyrosinase and gp100 linked to DC-LAMP, and TriMix smRNA. TriMix-DC are cryopreserved and 24.106 viable DC are administered by 4 ID/IV-injections q2w, and a 5th-injection on w16. The number of IV administered DC was escalated from 4.106, over 12.106, to 20.106 in cohort 1, 2 and 3 respectively. Tumor response assessments are performed by 18F-PET/CT at baseline and in w8, 16 and 24. Immunomonitoring is performed by analysis of DTH infiltrating lymphocytes (DIL) at an ID injection site. Results: 11 pts (9M/2F; med age 54, range 40-77) with stage IV pretreated melanoma, have initiated study treatment. TriMix-DC related AE's: gr2 local skin injection site reactions (all pts); fever & lethargy (gr1, 1 pt in cohort 1); chills (gr2, 2 pts in cohort 3). Vaccine-specific DIL were documented in 6/7 pts (5/7 pts had a CD137+CD8+ and 4/7 pts a CD4+ T-cell response). As of Jan 2011, 8 pts were evaluated for response (RECISTv1.1): 1 CR, 1 PR, 3 SD, and 3 PD; regression of metastases occurred in lung- (2 pts) and lymph node metastases (3 pts); 4/8 pts remain progression-free after respectively 3.1, 3.6, 7.7 and 8.2 mths of follow-up. Conclusions: TriMix-DC therapy by combined IV/ID administration is feasible, safe, and immunogenic. Durable anti-melanoma activity is observed across the investigated IV-dose levels and compares favorably with our prior observations with TriMix-DC administered ID-only.
AB - Background: Autologous monocyte derived dendritic cells (DC) electroporated with synthetic messenger RNA (smRNA) encoding CD40 ligand, a constitutively active TLR4, and CD70 (TriMixDC), together with smRNA encoding fusion-proteins of a HLA-class II targeting signal and a melanoma associated antigen are immunogenic when administered ID (Wilgenhof et al. ASCO AM 2009). The TriMixIDIV clinical trial investigates the safety, immunogenicity, and activity of combined ID and IV administration in patients with pretreated melanoma. Methods: Following leukapheresis, immature DC (derived from adherent PBMC cultured for 6 days in IL-4/GM-CSF supplemented medium) are electroporated with smRNA encoding MAGE-A3, MAGE-C2, Tyrosinase and gp100 linked to DC-LAMP, and TriMix smRNA. TriMix-DC are cryopreserved and 24.106 viable DC are administered by 4 ID/IV-injections q2w, and a 5th-injection on w16. The number of IV administered DC was escalated from 4.106, over 12.106, to 20.106 in cohort 1, 2 and 3 respectively. Tumor response assessments are performed by 18F-PET/CT at baseline and in w8, 16 and 24. Immunomonitoring is performed by analysis of DTH infiltrating lymphocytes (DIL) at an ID injection site. Results: 11 pts (9M/2F; med age 54, range 40-77) with stage IV pretreated melanoma, have initiated study treatment. TriMix-DC related AE's: gr2 local skin injection site reactions (all pts); fever & lethargy (gr1, 1 pt in cohort 1); chills (gr2, 2 pts in cohort 3). Vaccine-specific DIL were documented in 6/7 pts (5/7 pts had a CD137+CD8+ and 4/7 pts a CD4+ T-cell response). As of Jan 2011, 8 pts were evaluated for response (RECISTv1.1): 1 CR, 1 PR, 3 SD, and 3 PD; regression of metastases occurred in lung- (2 pts) and lymph node metastases (3 pts); 4/8 pts remain progression-free after respectively 3.1, 3.6, 7.7 and 8.2 mths of follow-up. Conclusions: TriMix-DC therapy by combined IV/ID administration is feasible, safe, and immunogenic. Durable anti-melanoma activity is observed across the investigated IV-dose levels and compares favorably with our prior observations with TriMix-DC administered ID-only.
KW - TRIMIX-DC
KW - MELANOMA
M3 - Meeting abstract (Journal)
SN - 0732-183X
VL - 29
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - s15
M1 - 2519
ER -