Enhancing Solid Tumor lmmunotherapy with Targeted siRNA Delivery

Abstract
To address the significant challenges of immunotherapy for solid tumors, Absco Therapeutics (AbscoTx) has
developed a novel intratumoral delivery system utilizing the Oncolymer™ platform. The need for new effective
approaches to deliver therapeutics into tumors and activate the potential of immunotherapy for solid tumors is
particularly evident in microsatellite instability-low (MSI-low) cancers, such as most colorectal carcinomas
where immune-checkpoint inhibitors show efficacy in less than 5% of patients. The Oncolymer platform can
revolutionize tumor therapy by enabling sustained, localized delivery of a synergistic combination of
therapeutic agents, including immune-sensitizing siRNA and the TLR7 agonist imiquimod, to reengineer the
tumor immune microenvironment (TIME) and stimulate systemic anti-tumor immunity. The core innovation of
the Oncolymer platform lies in its thermoresponsive hydrogel technology, based on a PLGA and PEG polymer
solution that transforms from room-temperature liquid to a solidified depot upon injection, and an
FDA-approved imaging agent, to accurately target tumors under real time image guidance using standard
clinical interventional techniques. The system is designed to maximize sustained local effect for durable
immune education while minimizing systemic drug exposure. Preclinical studies have validated the potential of
this platform. In a murine model of colorectal cancer, a single injection of the imiquimod-only Oncolymer
formulation, combined with systemic checkpoint inhibitors, led to complete tumor regression in 46% of cases,
with evidence of long-term immune memory and resistance to rechallenge. Additionally, pharmacokinetic
studies demonstrated that the active drug remained concentrated within the tumor for at least five days at
1000-fold its serum levels, further illustrating the platform's capacity for localized, sustained delivery. AbscoTx
has furthermore developed the capability to encapsulate and deliver nucleic acids, including siRNA, with the
Oncolymer system to surmount the issues of targeted RNA delivery to tumors. This enables localized release
of siRNA in a format that provides for both protection and activity, and solves the critical challenge of targeted
delivery that has limited the potential of nucleic acid therapeutics, particularly in cancer. The proposed Aims will
combine intratumoral delivery of a small molecule and siRNA to create a combination drug with the potential to
act as potent monotherapy treatment of local and metastatic tumors. This will be evaluated for in vitro release
(Aim 1), in vivo PK and bioactivity (Aim 2), and efficacy in a mouse model of colorectal cancer (Aim 3). This
innovative approach not only holds promise for improving outcomes in immune-resistant solid tumors but also
a scalable solution for integrating siRNA therapeutics into oncology. The platform’s adaptability allows for the
incorporation of diverse nucleic acid payloads, broadening its potential application to other tumor types and
paving the way for strategic pharmaceutical partnerships.

Grant Number: 1R43CA306686-01
NIH Institute/Center: NIH
Principal Investigator: David Altreuter