Antibody-based immunotherapy (e.g. check point inhibitors) has emerged as one of the most promising directions in clinical oncology.1 These agents and their synergistic combinations show promising pre-clinical efficacy in a wide range of incurable malignancies, including malignant brain tumors – one of the deadliest types of cancer known.2 Unfortunately, translation of most of these approaches remains difficult due to challenges in controlling the bio-disposition of antibody-based drugs.3 Owing to their unfavorable systemic biodistribution, high dose regimens are required to attain and maintain therapeutic drug concentrations in tumors.4, 5 Such regimens yield high off-target drug exposure and deleterious systemic toxicity, posing a difficult barrier to clinical translation.3, 6 We aim to develop a new approach for placing the bio-biodisposition of therapeutic antibodies under focused ultrasound control. This approach harnesses our newly developed messenger RNA (mRNA) nanoparticles, mRNAresp, that facilitate transfection via an ultrasound-controlled gating mechanism. Our strong preliminary data reveal that mRNAresp allow leveraging focused ultrasound to direct expression of mRNA-encoded proteins to specific tissue sites with minimal expression in off-target tissues. In this study, we will assess the applicability of this approach for directing expression of mRNA-encoded antibody therapeutics to brain tumors and determine the ensuing efficacy and toxicity. We expect to demonstrate that this approach has the capacity to offer anti-tumor efficacy that is comparable to standard protein-based antibody treatments, while significantly reducing off-target toxicity. Successful completion of the project goals will yield a clinically viable strategy to unlock the full potential of therapeutic antibodies for combating refractory malignancies.
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