Background Adoptive T Cell Therapies (ACT) are promising anti-cancer approaches for treatment of solid tumors, but still face challenges in achieving complete responses. ACTengine IMA203 is an investigational ACT for the treatment of solid tumors in HLA A*02:01 positive patients with advanced or recurrent cancers. The IMA203 product consists of genetically-modified patient T cells that express a recombinant T cell receptor targeting a HLA-A*02:01-restricted Preferentially Expressed Antigen in Melanoma (PRAME) epitope on cancer cells. In an ongoing Phase 1 trial, IMA203 has shown a favorable safety profile with an confirmed overall response rate of 55% in patients with melanoma. To potentially further enhance its clinical efficacy, IMA203 will be combined with a lipid nanoparticle (LNP) encapsulated mRNA encoding the IMA203 PRAME-derived target peptide. Here we present preclinical proof-of-concept data supporting this ACT-mRNA combination and introduce the trial design for a First-In-Human (FIH) Phase 1 clinical combination study.

Methods Human monocyte-derived dendritic cells (moDCs) were transfected with increasing doses of LNP-formulated mRNA constructs and co-cultured with IMA203 T cells for up to 96h. Expression of T cell surface activation markers, CD25, CD69 and CD137, was quantified by flow cytometry.Interferon gamma (IFN-γ) secretion was measured by enzyme-linked immunosorbent assay (ELISA) 24h post-transfection. Cell proliferation was monitored by absolute quantification of cell counts at different time points. Non-transduced T cells and mock transfected moDCs were used as negative controls.

Results Upon co-culture with moDCs transfected with the different mRNA-LNPs, IMA203 T cells upregulated the expression of all evaluated activation markers and produced increased IFN-γ concentration in an mRNA-LNP dose-dependent manner. Concurrently, IMA203 T cells proliferated, leading to an increase in CD8+ IMA203 T cell counts. In contrast, these effects were not observed in the negative controls, thus confirming the antigen-, TCR- and dose-dependent nature of the response. Based on the results, a lead mRNA construct was selected to be advanced to the FIH trial.

Conclusions We have established preclinical proof-of-concept and showed that LNPs containing PRAME-encoding mRNA can strongly activate IMA203 T cells and induce their proliferation. A FIH clinical combination study of IMA203 with the selected mRNA-LNP construct is planned. For the FIH phase 1 trial, the safety, tolerability and efficacy of the combination therapy will be evaluated in up to 15 patients with advanced or recurrent cutaneous melanoma and synovial sarcoma.