Many diseases are caused by insufficient expression of mutated genes and would benefit from increased expression of the corresponding protein. However, in drug development, it has been historically easier to develop drugs with inhibitory or antagonistic effects. Protein replacement and gene therapy can achieve the goal of increased protein expression but have limitations. Recent discoveries of the extensive regulatory networks formed by non-coding RNAs offer alternative targets and strategies to amplify the production of a specific protein. In addition to RNA-targeting small molecules, new nucleic acid-based therapeutic modalities that allow highly specific modulation of RNA-based regulatory networks are being developed. Such approaches can directly target the stability of mRNAs or modulate non-coding RNA-mediated regulation of transcription and translation. This Review highlights emerging RNA-targeted therapeutics for gene activation, focusing on opportunities and challenges for translation to the clinic. Many diseases involve reduced or absent levels of a particular protein and would benefit from therapies that increase gene expression. In their Review, Khorkova et al. discuss the growing range of RNA-targeted therapies in development that aim to boost gene expression, including nucleic acid-based therapeutics targeting the complex regulatory network of non-coding RNA species. 

/pdf/amplifying-gene-expression-with-rna-targeted-therapeutics-jxbim179.pdf

Amplifying gene expression with RNA-targeted therapeutics

novel immunotherapy targeting the myeloid cell lineage that has shown promising clinical activity in hepatocellular carcinoma, and preclinical activity in models of solid tumour cancers in combination with ICIs. We previ-ously reported dose escalation data for MTL-CEBPA in combination with ICI from TIMEPOINT, an ongoing multi-centre phase 1/1b study (NCT-04105335) evaluating the safety, PK, immunomodulation and clinical activity of MTL-CEBPA in combination with pembrolizumab in patients with anti-PD(L)1 naïve advanced solid tumours for whom no standard therapy is

/pdf/850-interim-results-for-phase-1b-dose-expansion-of-mtl-cebpa-3phbov5x.pdf

850 Interim results for phase 1b dose expansion of MTL-CEBPA in combination with pembrolizumab in patients with advanced solid tumour malignancies


 Despite significant advances in outcomes with immunotherapy, most cancer patients do not benefit from currently approved immune checkpoint inhibitors (ICI). The reasons for ICI resistance are multi-faceted and suggest that additional immunomodulation is required to improve outcomes. MTL-CEBPA is a novel immunotherapy based on RNA activation that upregulates expression of a master myeloid transcription factor, CEBPA. The small activating RNA for CEBPA is encapsulated within a NOV340 liposome that targets the myeloid cell lineage. MTL-CEBPA has shown favorable safety and promising clinical activity in combination with tyrosine kinase inhibitors (Sorafenib) in hepatocellular carcinoma (NCT-02716012) [Hashimoto et al, CCR 2021; Sarker et al, CCR 2020]. We recently reported preliminary clinical data from the ongoing multi-center phase 1 TIMEPOINT study (NCT-04105335) evaluating the safety, pharmacokinetics, immunomodulation, and clinical activity of MTL-CEBPA in combination with pembrolizumab in patients with solid tumors who have exhausted standard therapy. This demonstrated a favorable safety profile and initial clinical activity [Plummer et al, JITC 2021]. Here we report the findings from a biomarker pharmacodynamic analysis of paired baseline and cycle 2 tumor sample biopsies in 23 patients from the TIMEPOINT trial. Brightplex® IHC and digital pathology analyses of the samples for myeloid and T cell panels were undertaken, alongside gene expression (Nanostring I/O 360). Prior to study treatment, nine patients out of 23 had an immune cold tumor microenvironment (TME) at baseline as measured by the Immunosign®21 score. Following the combination of MTL-CEBPA with pembrolizumab, seven of these patients converted to an inflamed TME by Immunosign®21 (P=0.008). This change in the TME was associated with infiltration of CD8 and cytotoxic T cells (CD8+, GrzB+, Ki-67+) (P=0.1). GSEA analysis indicated that a Tstem-like signature was enriched post-treatment. A Brightplex® IHC analysis of myeloid cells in these patients indicated that, post treatment, there was a significant influx of HLA-DR+ myeloid cells into the TME (P=0.04). We also observed a significant increase in the expression of CXCL9, 10, and 11. The remaining 14 patients had an inflamed TME at baseline. Here, we also observed an increase in HLA-DR+ cells, T cells, and chemokines, though to a lesser extent. Further, however, in these inflamed tumors—which have significantly greater infiltration of myeloid-derived suppressor cells (MDSCs) than desert tumors—we observed a reduction in 8/10 patients with detectable PMN-MDSCs (P=0.1) post treatment, consistent with the mechanism of action of CEBPA. An expression signature based on 18 genes significantly enriched for clinical response across all patients. Collectively, these data suggest a positive immunomodulatory TME effect of the combination of MTL-CEBPA with pembrolizumab. In both hot and cold TME tumors, the combination drives directed differentiation of progenitor monocytes into HLA-DR+ myeloid cells secreting chemokines that stimulate the ingress of T cells into the TME. We observe a significant positive correlation between the change in cytotoxic T cells and HLA-DR+ myeloid cells post treatment (P=0.004). These effects are most pronounced in cold tumors.
 Citation Format: Ruth Plummer, Mikael Sodergren, Brid Ryan, Ilian Tchakov, Nina Raulf, Rose Hodgson, CP Tan, Joanna P. Nicholls, Alison Adderkin, N Vasileiadou, Vikash Reebye, Tim Meyer, David J. Pinato, Debashis Sarker, Bristi Basu, Sarah Blagden, Natalie Cook, Jeff Evans, Jeffrey Yachnin, Cheng Ean Chee, Dan Li, Anthony El-Khoueiry, Maria Diab, Kai-Wen Huang, Marcus S. Noel, Bridget Keenan, Devalingam Mahalingam, Melanie Grosso, Denis Arnaud, Aurelie Auguste, Jan Storkholm, Iain McNeish, Robert Habib, John J. Rossi, Nagy Habib. MTL-CEBPA in combination with pembrolizumab converts an immune desert to an inflamed TME in solid tumors resistant to checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB192.

Abstract LB192: MTL-CEBPA in combination with pembrolizumab converts an immune desert to an inflamed TME in solid tumors resistant to checkpoint blockade

Drugging transcription factors with small activating RNAs: A novel approach for enhancing bone marrow therapy for monogenic rare diseases

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850 Interim results for phase 1b dose expansion of MTL-CEBPA in combination with pembrolizumab in patients with advanced solid tumour malignancies

Abstract LB192: MTL-CEBPA in combination with pembrolizumab converts an immune desert to an inflamed TME in solid tumors resistant to checkpoint blockade

Drugging transcription factors with small activating RNAs: A novel approach for enhancing bone marrow therapy for monogenic rare diseases