Trimix Advances to Next Stage in Clinical Trials
The tripartite mRNA technology has completed its phase 1b study for direct, intranodal injections in adjuvant melanoma patients
4 Mar 2019eTheRNA immunotherapies, a clinical-stage company developing cancer immunotherapies based on its proprietary mRNA TriMix platform, has announced the completion of the high-dose cohort of its Phase 1b study (E011-MEL) evaluating ECI-006 (TriMix with tumor specific antigens) in an adjuvant setting in melanoma patients after surgical removal of lesions. The E011-MEL study confirms the feasibility of developing mRNA immunotherapy for direct injection intranodally, in addition to a previously used dendritic cell infusion-based approach.
The E011-MEL Phase 1b study was designed to evaluate intranodal (injection into the inguinal lymph nodes) administration of ECI-006 in adjuvant melanoma patients. ECI-006 is a TriMix-based immunotherapy boosted with mRNA encoding melanoma tumor-specific antigens. The study comprises a low-dose and a high-dose cohort, each enrolling 10 patients. Investigative centers were in Belgium and Spain. The objective of the study is to assess safety and tolerability of mRNA administered intranodally and to seek evidence of immune-stimulation.
Completion of enrolment of the low-dose cohort was reported previously in March 2018, along with initial safety data. No adverse safety signals were observed in the low-dose cohort, which has already completed its dosing phase.
Today, the company reports completion of patient recruitment for the high-dose cohort. No adverse safety signals were observed in the high-dose cohort either. Results from the immunomonitoring of the immunological responses elicited by ECI 006 will be presented at a later date.
Dr. Bertil Lindmark, Chief Medical Officer, eTheRNA immunotherapies commented: “With this study we have shown that intranodal injection of an mRNA based immunostimulatory vaccine is clinically feasible and well tolerated. This is an important result as it advances our strategy to develop mRNA-based immunotherapies to treat patients with cancer. The ECI-006 can effectively induce immune priming so that we may see amplified efficacy when combined with a checkpoint inhibitor”.
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The TriMix Technology
eTheRNABoosting immune response through the dendritic cell pathway in a targeted, safer and sustainable way eTheRNA’s TriMix contains three naked mRNA molecules: caTLR4 (that activates the immune system as it evokes dendritic cells to present antigens to the CD4/CD8 T-cells), CD40L (that induces the dendritic cells to initiate the antigen-specific action of the CD4 T-cells), and CD70 (that induces the dendritic cells to initiate the immune system of the CD8 T-cells). TriMix is unique in the way it uses these three mRNA molecules to circumvent some of the main obstacles faced by other immunotherapy concepts when attempting to induce the proliferation of T-cells into either mature helper T-cells or cytotoxic T-cells (i.e. the ultimate 'soldiers' of the immune system that fight cancer cells and infectious agents): The first attempts used specific antigens (unique molecules of the cancer cell or infectious agent) to induce an immune response. Many mediators for presenting the antigens are investigated: cancer cells, part of cells, DNA or proteins/peptides. To date, none of them yielded satisfactory results in the induction of an immune response that is sufficiently strong for resulting in a clinical response — not even when combined with adjuvants. Moreover, the safety aspects of some of these approaches (inclusion of genetic materials) remains an open question. The attention then shifted to using the patient's own dendritic cells as key mediator to trigger an effective immune response. Dendritic cells that were simply loaded ex vivo with tumor-associated antigens did effectively induce some immune response in patients, and even some clinical response - though unfortunately not sufficiently strong. TriMix overcomes these limitations by providing an additional triple boost: TriMix enhances the activation and maturation of dendritic cells, TriMix stimulates the processes that lead to activated helper T-cells, and TriMix also promotes the processes that result in activated cytotoxic T-cells. The mRNA constructs of the TriMix-based immunotherapy are coding for both the tumor-specific antigens as well as for three unique and crucial proteins that jointly stimulate the patient’s dendritic cells to produce a more potent and larger population of cytotoxic and helper T-cells. In preclinical and phase I/IIa studies in advanced melanoma, the TriMix cellular product - stand-alone or combined with a checkpoint inhibitor - demonstrated a unique capability for enhancing dendritic cells to elicit a powerful immune response, a promising clinical response and an increased disease-free survival rate. Thanks to the very good tolerability profile of this product, combination with other cancer drugs is a possibility.