Novel RNA-nanoparticle vaccine for the treatment of early melanoma recurrence following adjuvant anti-PD-1 antibody therapy.

Abstract

TPS9609 Background: Melanoma is a major public health concern with an anticipated increase in prevalence and incidence in the coming years. Early detection and surgical management remain the mainstay of treatment of early-stage disease and use of adjuvant immunotherapy has improved outcomes for patients with more aggressive (IIB-IIC) local disease or those with lymph node involvement (IIIA-IIID). Based on the tolerability and efficacy across subjects with both BRAF mutated and wildtype melanoma anti-PD1 (aPD1) therapy with either nivolumab or pembrolizumab are considered first line treatment in this setting. Adjuvant aPD1 therapy has significant improvement in relapse free survival (RFS) yet 25-30% of subjects will have disease recurrence within 1 year of surgery. When disease recurs, the response rate to immunotherapy is significantly reduced, re-challenged with aPD1 therapy has shown an Objective Response Rate (ORR) of zero and a marginally better response to CTLA-4 blockade. Novel strategies are needed for this at-risk population with early aPD1 resistance. To address this need we have developed a novel multi-lamellar lipid-nanoparticle complexed with total-tumor derived mRNA administered intravenously to restore responsiveness to aPD1 through reprogramming the tumor microenvironment (TME) bridging an innate and adaptive immune response. We have designed a clinical trial in which patients who progress on while on aPD1 therapy or within 6 months of therapy will have tumor sampled and a personalized lipid-nanoparticle vaccine generated. This vaccine is then administered IV for a total of 3 doses spanning 6 weeks to reprogram the TME and restore response to aPD1 which will be resumed on completion of vaccine series. This phase I study will assess initial feasibility and safety of vaccine generation, utilize ctDNA surveillance as early detection of adjuvant failure, and provide essential biologic information on immunotherapy resistance to aPD1 therapy. Methods: We have designed a modified 3+3 phase I clinical trial that will enroll subjects who have evidence of progressive disease (PD) by ctDNA and/or RECIST 1.1 criteria while receiving adjuvant aPD1 therapy, or those who progress within 6 months of completion of treatment for stage IIB-IIID melanoma. The goal of this study is to assess safety, tolerability, and feasibility of tumor specific RNA-LPs. Important biological correlates will also be collected and analyzed including tumor tissue sampling at initial time of checkpoint resistance and following vaccination series to identify key changes to the TME and tumor induced by lipid-nanoparticle vaccine administration. Clinical trial information: NCT05264974 .