Phase I/Ib study with INT-1B3, a novel LNP-formulated micro-RNA (miR-193a-3p mimic) therapeutic for patients with advanced solid cancer.

Abstract

TPS2666 Background: MicroRNAs (miR) are naturally-occurring small non-coding RNA molecules involved in the regulation of gene expression and their dysregulation plays a fundamental role in several pathological conditions including cancer. The miR-193a-3p acts as a tumor suppressor and is downregulated in many cancer types. INT-1B3 is a novel lipid-nanoparticle (LNP) formulated 1B3, a 22-nucleotide double stranded chemically-modified miR-193a-3p mimic. INT-1B3 showed significant tumor growth inhibition in a large panel of human and syngeneic tumor models. It directly targets tumor cells and the tumor microenvironment by specific modulation of multiple signaling pathway components. Furthermore, in syngeneic mice models for e.g. TNBC (4T1) and HCC (H22), INT-1B3 was able to modulate the immune tumor microenvironment by turning ‘cold’ tumors into ‘hot’ tumors via upregulation of cytokines (e.g., IL-2 and IFN-g), decreasing immunosuppressive cells/Treg (e.g., CD4+ /LAG3+ and CD3+ /FoxP3+) and triggering cytotoxic CD8+ T cell-mediated long-term memory immune protection against re-challenge with tumor cells. These preclinical results suggest potential clinical benefit in a broad range of cancer indications, and a reduced potential to develop drug resistance due to its multi-targeted mode of action. Methods: This is a 2-part, multi-center, open-label, multiple ascending dose, first-in-human, clinical study to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of INT-1B3 in the treatment of patients with advanced solid tumors. The phase 1 part follows a ‘hybrid’ 3+3 study design in ‘all-comer’ cancer patients enrolled and treated in cohorts to define the recommended phase 2 dose (RP2D). Upon completion of the dose escalation phase of the study, 2 expansion cohorts are planned to further confirm the safety, tolerability, and preliminary efficacy of the RP2D of INT-1B3 in patients with hepatocellular carcinoma and triple negative breast cancer. Major eligibility criteria include evaluable disease according to RECIST 1.1 and no more than one prior line of anti-PD-1/PD-L1 therapy. Patients will receive INT-1B3 via 60-min i.v. infusions twice a week in 21-day cycles. The first patient was enrolled on January the 14th 2021. Clinical trial information: NCT04675996.

Preclinical testing of miRNA-193b-3p mimic in acute myeloid leukemias

“…Similarly, retrieving miR-193b function can potentially affect several pathways, including the MAPK/ERK pathway, which is constitutively active in leukemia [ 4 ], and the well-known oncogene c-KIT, which is recurrently mutated in AML and is linked to therapy resistance, especially following relapse. Similar LNPs formulations encapsulating miR-193a-3p mimics (INT-1B3) are currently undergoing clinical trials for advanced solid tumors [ 13 ]. Both miR-193b and miR-193a have tumor suppressive activity and are downregulated in malignant tissues [ 4 , 13 ].…”

“…Similar LNPs formulations encapsulating miR-193a-3p mimics (INT-1B3) are currently undergoing clinical trials for advanced solid tumors [ 13 ]. Both miR-193b and miR-193a have tumor suppressive activity and are downregulated in malignant tissues [ 4 , 13 ].…”