Clinical trials with MRNA electroporated dendritic cells for stage III/IV melanoma patients
- 280 Downloads
KeywordsMelanoma Melanoma Patient CD40 Ligand Advanced Melanoma Inflammatory Skin
TriMixDC-MEL consists of autologous monocyte-derived DC that are electroporated with synthetic mRNA encoding CD40 ligand, a constitutively active TLR4, CD70 and fusion proteins of DC.LAMP with 4 melanoma associated antigens (MAGE-A3, MAGE-C2, tyrosinase and gp100).
TriMixDC-MEL was investigated in patients (pts) with pretreated advanced melanoma, either as a single agent (Phase Ib; NCT01066390) or combined with IPI (Phase II; NCT01302496; 10 mg/kg q3wks x4) and also in melanoma pts who are disease free following local treatment of macrometastases. TriMixDC-MEL was administered by the IV and ID-route (4 to 5 admin; 4.106-ID/20.106-IV).
In pts with unresectable AJCC stage III or IV melanoma, respectively 15 and 39 pts were treated in the Phase Ib and the –II trial. DC-related AEs consisted of local inflammatory skin reactions at the DC-injection site (all pts), grade (gr) 2 acute post-IV injection chills in 20% and 38%, and gr 1-2 flu-like syndrome in 53% and 85% of pts treated respectively with DC or DC+IPI. Grade 3 or 4 irAEs occurred in 36% of DC+IPI treated pts. ORR for DC: 27% (2 CR, 2 PR; 3 are ongoing after > +51 mths) and 38% for DC+IPI (8 CR, 7 PR; 8 are ongoing after > +16, mths). Median PFS and OS are respectively 5 (95% CI 0–10) and 14 mths (95% CI 5–23) for DC and 6.2 (95% CI 2-10) and 13 mths (95% CI, 9-18) for DC+IPI. The 1, 2 and 3y OS% for DC+IPI were: 59% (95% CI 43-74), 38% (95% CI, 23-53), and 34% (95% CI, 19-50). Treatment with TriMixDC-MEL, especially in combination with IPI, is tolerable and results in a high rate of durable tumor responses. In the adjuvant setting (NCT01676779), 41 patients were randomized between the TriMixDC-MEL treatment arm (n=21) and control-arm (n=20). Baseline characteristics were well balanced between both groups. After a median follow-up of 18 mths (range 5 to 30 mths) 20 patients experienced a non-salvageable melanoma recurrence (6 on the DC- and 14 on the control-arm). The rate of patients who were disease-free at 1 year (evaluable population = 35 patients) was higher in the TriMixDC-MEL treated group (65% [95%CI 42-87] vs. 34% [13-55]). TriMixDC-MEL was well tolerated (no grade >3 AE).
The results of this non-comparative randomized controlled Phase II clinical trial of TriMixDC-MEL ID/IV versus observation support the further evaluation of TriMixDC-MEL as a well-tolerated adjuvant therapy for melanoma patients following the resection of macrometastases.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.