57P - SENDER™ Directed LNP Delivery of mRNA for In Situ generation of highly potent CAR T Cells

Background

CAR T cell therapies have shown success in cancer treatment, especially in hematologic malignancies. However, scalability, manufacturing, and inpatient treatment limit their broad use. A non-viral, off-the-shelf solution is key to overcoming these barriers, especially for indications outside oncology. Building on mRNA LNPs for in-vivo CAR T delivery, we developed SENDER (Specific Engager Nanoparticle DelivERy), a novel approach to redirect LNPs for targeted mRNA delivery to immune cells. SENDER proteins non-covalently bind to LNPs, redirect them to T cells, and block protein corona formation, reducing off-target accumulation in the liver.

Methods

The SENDER technology delivers LNP to T cells, ensuring specific mRNA delivery while preventing off-target accumulation. The design was tested both in vitro, for its ability to deliver mRNA payloads to T cells, and in vivo, using a humanized mouse model to evaluate tumor clearance and CAR T cell expression.

Results

CD3-targeting SENDER proteins effectively transfected both CD4⁺ and CD8⁺ T cells, while CD8-targeting SENDER proteins transfected only CD8⁺ T cells. The SENDER platform demonstrated superior targeting capabilities, allowing efficient mRNA delivery of multiple CARs and armoured elements to T cells. In a Nalm6 xenograft model, repeated doses of a novel humanised anti-CD19 mRNA CAR delivered via SENDER-LNPs resulted in rapid and sustained tumor clearance, achieved with a fraction of the dose typically required for other LNP targeting approaches. Off-target delivery to the liver was significantly reduced, highlighting the efficiency of the SENDER platform.

Conclusions

- The SENDER platform enables targeted in situ CAR T cell generation via non-viral mRNA delivery whilst avoiding lymphodepletion - Approach allows for the redirection of LNPs specifically to T cells, reducing off-target effects - In vivo studies demonstrated rapid and sustained tumor clearance with a lower -dose of LNPs compared to other targeting methods. - Technology offers a scalable, redosable alternative to conventional CAR T therapies - The modular nature of SENDER allows adaptation for various therapeutic areas, using different targeting proteins and payloads.

Legal entity responsible for the study

Chimeris UK Ltd.

Funding

Chimeris UK Ltd.

Disclosure

B. Ma, K. Hu, R. Karatill, R. Williams, J. Hayre, S. Srivastava, S. Cordoba, S. Onuoha: Financial Interests, Institutional, Stocks/Shares: Chimeris UK Ltd.