A phase I study (E011-MEL) of a TriMix-based mRNA immunotherapy (ECI-006) in resected melanoma patients: Analysis of safety and immunogenicity.

Abstract

2641 Background: ECI-006 is a combination of TriMix (mRNAs encoding for dendritic cell [DC] activating molecules [CD40L, CD70 and caTLR4]), and mRNAs encoding for melanoma-specific tumor-associated antigens (TAAs): tyrosinase, gp100, MAGE-A3, MAGE-C2, and PRAME. DCs transfected ex vivo with TriMix and TAAs mRNAs showed significant clinical activity in combination with ipilimumab in metastatic melanoma without increasing toxicity. This study aims to assess the safety and immunogenicity of ECI-006 vaccine administered intranodally (i.n.) in an adjuvant setting for patients with resected melanoma. Methods: Twenty patients who underwent resection of stage IIc/III/IV cutaneous melanoma received 5 administrations of ECI-006 (either 600 µg or 1800 µg [n = 10, each]) injected i.n. on Day 1 and after 2, 4, 6 and 14 weeks. Treatment-emergent adverse events (TEAEs) were graded using CTCAE version 4.0.3. Blood samples for immune monitoring (ELISPOT and intracellular cytokine staining [ICS]) were collected pre-dose and at weeks 4, 7, 14 and 15. Results: Nineteen patients completed the treatment. One patient in the low dose group discontinued the study after 4 doses due to disease relapse. Administration of ECI-006 was well tolerated. No serious adverse events or TEAEs Grade 3 or higher were reported. Of all TEAEs, myalgia and fatigue were the most reported in 3 (15%) and 5 (25%) patients, respectively. ELISPOT and ICS were performed on T cells pre-stimulated in vitro for 10-12 days, using a previously in-house validated protocol. Vaccine-induced immune responses according to predefined criteria were detected in 4/10 and 3/9 patients treated with the low and high dose, respectively. Samples from these patients are currently being subjected to T-cell receptor repertoire analysis. Conclusions: Among patients undergoing resection of stage IIc/III/IV melanoma, i.n. administration of ECI-006 at 600 or 1800 µg was generally well tolerated. ECI-006 demonstrated to be immunogenic in a proportion of patients. These results warrant further development of ECI-006 in combination with anti-PD-1 therapy in melanoma patients. Clinical trial information: NCT03394937.

mRNA therapeutics in cancer immunotherapy

“… Prostate cancer NCT01817738 (I/II, randomized) None 2012 Terminated [ 42 – 44 ] NCT02140138 (II, randomized) Radical prostatectomy 2014 Terminated (after enrollment of 35/36 patients) eTheRNA mRNA encoding tyrosinase, gp100, MAGE-A3, MAGE-C2, and PRAME and TriMix (CD40L, CD70 and caTLR4) mRNA (i.n.) Melanoma NCT03394937 (I) None 2018 Recruiting [ 45 ] Ludwig Institute for Cancer Research, CureVac AG, Böhringer Ingelheim RNActive encoding NY-ESO-1, MAGE-C1, MAGE-C2, TPBG, survivin, MUC1 (i.d.) Meatastatic NSCLC NCT03164772 (I/II) Durvalumab (antagonistic anti-PD-L1), Tremelimumab (antagonistic anti-CTLA-4) 2017 Recruiting Merck Sharp & Dohme Corp. LNP-formulated mRNA encoding different KRAS mutations (i.m.)…”

“…Non-formulated or “naked” mRNA administered intradermally or into lymph nodes (intranodally) has been shown to prime T-cell responses in mice [ 85 – 88 ] and humans [ 45 , 89 , 90 ]. The rationale for intranodal injection is to deliver the vaccine directly into the area of T-cell priming for uptake by resident DCs.…”

“…In another phase I study of 20 melanoma patients (NCT03394937), intranodal injection of tyrosinase, gp100, MAGE-A3, MAGE-C2, and melanoma antigen preferentially expressed in tumors (PRAME)-encoding mRNA together with TriMix mRNA was well tolerated. As observed by IFNy ELISpot and intracellular cytokine staining, T-cell responses against at least one TAA were induced in 35% of patients [ 45 ].…”

mRNA-Based Cancer Vaccines: A Therapeutic Strategy for the Treatment of Melanoma Patients

“…Few clinical trials concerning direct TriMix injection have been conducted. One trial aiming to assess the immunogenicity and safety of the ECI006 vaccine (a combination of TriMix and MAA-encoding mRNA) via intranodal administration was initiated in 2017 (NCT03394937) [184]. In this study, no serious adverse events occurred in the postvaccination period, indicating the good tolerability and safety of ECI006.…”

The Limitless Future of RNA Therapeutics

“…Currently, there are several cell-based therapies that have reached clinical trials and employ mRNA. For example, TriMix-based immunotherapy (ECI-006) is a combination of mRNAs encoding DC-activating molecules (CD40L, CD70, and caTLR4) and melanoma-specific tumor-associated antigens (tyrosinase, gp100, MAGE-A3, MAGE-C2, and PRAME) ( Arance Fernandez et al, 2019 , p. 011) that are transfected into autologous DCs ex vivo . This therapy has demonstrated significant clinical activity in combination with ipilimumab without increasing regimen toxicity in metastatic melanoma ( De Keersmaecker et al, 2020 ).…”