Leucid Bio has received clinical trial authorization from the UK Medicines and Healthcare products Regulatory Agency (MHRA) to commence its Phase 1/2 AERIAL trial evaluating LEU011, an innovative Chimeric Antigen Receptor T-cell (CAR-T) therapy for the treatment of adults with relapsed or refractory solid tumors.
The London-based biotechnology company is on track to dose the first patient during the fourth quarter of 2023, with preliminary first-in-human data expected in 2024. This milestone advances Leucid's proprietary Lateral CAR platform technology, which aims to overcome the limitations of conventional CAR-T therapies in treating solid tumors.
Novel Lateral CAR Platform Technology
LEU011 utilizes Leucid Bio's proprietary lateral CAR platform, which differentiates itself from traditional CAR-T approaches through its unique design. While conventional CAR-T products arrange costimulatory domains in a linear fashion, the lateral CAR platform positions complementary signaling domains across the cell membrane, mimicking the natural configuration found in immune cells.
This innovative architecture is designed to enhance tumor targeting, selectivity, and engagement. Dr. John Maher, Chief Scientific Officer at Leucid Bio, pioneered CD28-based second-generation CAR technology in human T-cells 20 years ago and has continued to advance the field with this lateral configuration approach.
Targeting NKG2D Ligands for Broad Tumor Application
LEU011 is an autologous CAR-T therapy that incorporates an NKG2D receptor capable of recognizing one or more of eight human NKG2D ligands. These ligands are expressed on transformed, infected, or damaged cells and are reported to be present on more than 80% of human tumors, giving LEU011 potential applications across multiple cancer indications.
"The design of the AERIAL trial, which was inspired by our exciting preclinical data for LEU011, is aimed at assessing the broad potential of the innovative cell therapy across several solid tumors expressing NKG2D ligands," stated Dr. John Maher.
Promising Preclinical Results
In preclinical studies, LEU011 has demonstrated impressive efficacy, showing a 95% overall response rate across 12 in vivo models representing six different tumor types. The therapy has shown potential therapeutic effects in models of colorectal, pancreatic, ovarian, and breast cancer, as well as mesothelioma.
Notably, LEU011 demonstrated prolonged disease-free survival compared to some other CAR-T treatments currently in clinical trials. In several models, rejection of secondary tumor rechallenge indicated functional persistence of the therapy—a critical factor for long-term efficacy.
AERIAL Clinical Trial Design
The Phase 1/2 AERIAL trial will follow an open-label, single-ascending dose design to identify the maximum tolerated dose of LEU011. Patients will receive the CAR-T therapy following preconditioning chemotherapy.
After completing the dose-escalation portion, the trial will advance to a dose expansion segment, enrolling patients with solid tumors expressing one or more NKG2D ligands. This broad approach aims to evaluate the therapy's potential across multiple tumor types.
Regulatory Recognition
In September 2022, LEU011 received the Innovation Passport designation as part of the Innovative Licensing and Access Pathway (ILAP) from the MHRA for the treatment of solid tumors expressing NKG2D ligands. Established in 2021, ILAP supports innovative approaches to the safe, timely, and efficient development of medicines to improve patient access.
"The MHRA's authorization and the ILAP designation for LEU011 highlight the strong potential of our proprietary lateral CAR T candidate LEU011 for the treatment of solid tumors," commented Filippo Petti, Chief Executive Officer at Leucid Bio. "The development of LEU011 demonstrates our commitment to pushing the boundaries in cell therapy research and underpins our dedicated focus on pursuing novel, durable therapies for cancer patients with limited treatment options."
Addressing Unmet Needs in Solid Tumor Treatment
While CAR-T therapies have revolutionized the treatment of certain hematological malignancies, their efficacy in solid tumors has been limited by various challenges, including tumor heterogeneity, the immunosuppressive microenvironment, and difficulties in identifying suitable target antigens.
Leucid Bio's approach with LEU011 aims to address these challenges through its lateral CAR design and by targeting NKG2D ligands, which are broadly expressed across multiple tumor types but have limited expression in healthy tissues.
As the company prepares to initiate the AERIAL study in the coming months, the field will be watching closely to see if this innovative approach can translate its promising preclinical results into clinical benefits for patients with limited treatment options.
