Background Melanoma is an increasing public health concern. Immune checkpoint inhibitors (ICI) has revolutionized the treatment of advanced melanoma. Unfortunately, in the adjuvant setting, up to 30% of subjects have disease recurrence within 1 year of treatment. Previous studies have shown that subjects who progress while on adjuvant ICI, or soon after completion, have a more aggressive course of disease that responds poorly to subsequent immunotherapy. One reason for the failure of ICI in the post adjuvant setting is the immune suppressive nature of the tumor microenvironment (TME) and lack of professional APC activation. These APCs remain in an inert state unable to present tumor antigens for immune detection due to lack of innate immune activation and inhibition from myeloid derived suppressor cells (MDSCs). We have developed a novel RNA-lipid particle (RNA-LP) vaccine that simultaneously penetrates and reprograms the TME while inducing a tumor specific adaptive response (figure 2). This vaccine utilizes novel engineering design that layers tumor derived mRNA into a lipid-nanoparticle ‘onion-like’ package along with pp65 full length lysosomal associated membrane protein (LAMP1) mRNA (figure 2). These RNA-LPs localize to the TME and activate multiple innate pathways thereby activating APCs and suppressing the function of MDSCs (figure 3). In this study we propose the use of subject derived RNA-LP vaccine in patients who progress on, or soon after completion of adjuvant ICI. We propose that through re-priming of the antitumor immune response and alteration of the TME we can restore the efficacy of ICI therapy. If effective, this treatment will revolutionize the management of this aggressive subset of melanoma. This study will also gather information into the mechanisms of early ICI resistance, identify novel biomarkers of innate resistance and response to treatment, and provides a cutting edge, personalized immunology approach to melanoma treatment.
Methods We have designed a 3+3 design phase I clinical trial (NCT05264974) assessing the manufacturing feasibility, safety, and maximum tolerated dose of RNA-LP vaccines in melanoma patients with early adjuvant ICI failure. Patients will receive a 3-part vaccine series, 2 weeks apart at time of progression then resume ICI therapy (figure 4). Major eligibility criteria include progression on ICI therapy or within 6 months of completion of adjuvant therapy. A minimum of 6 and maximum of 18 subjects will be treated. Secondary endpoints include overall response rate (ORR) and progression free survival rate (figure 5). Exploratory analysis will investigate the TME through single cell analysis pre and post vaccine series.
Trial Registration Novel RNA-nanoparticle Vaccine for the Treatment of Early Melanoma Recurrence Following Adjuvant Anti-PD-1 Antibody Therapy ClinicalTrials.gov Identifier: NCT05264974
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