Asmann, Qian Shi, Jordan Reynolds, Brian Necela, Nadine Norton, Michael Gustafson, Winston Tan, Rami Manochakia n, Yujie Zhao, Hani M. Babiker, Trevanne Rose Matthews Hew, Keith L. Knutson; Mayo Clinic Florida, Jacksonville, FL; Mayo Clinic, Rochester, MN; Mayo Clinic, Scott sdale, AZ Background: Though immunotherapy with anti-PD-1 immune checkpoint inhibitors (ICIs) has led to improvements in clinical outcomes in patients with cancer, when used as monotherapy inthe advanced setting, only 18-25% of patients respond to ICI. Notably, ICI frequently lacks anti-tumor activity in immune-cold cancers where T cell priming is missing. Recent breakthroughsin identifying personal neoantigens via a comprehensive analysis of cancer sequencing datahave brought increased attention to neoantigen cancer vaccines. Personalized cancer vaccines targeting neoantigens have shown early promise. While neoantigens have recently been in- vestigated in some cancer types, the current neoantigen prediction algorithms have oftenfocused on the MHC class-I subtype, single nucleotide mutations (SNM), small insertions anddeletions (INDEL). We recently developed an informatics workflow, REAL-neo, for the iden-tification, quality control (QC), and prioritization of both class-I and class-II human leukocyteantigen (HLA) bound neoantigens that arise from somatic SNM, INDEL, aberrant RNA splicing,and gene fusions, generating much more potent neoantigen candidates. Furthermore, wedemonstrated robust T-cell response and prolonged survival by combining ICI and cancer vaccines in preclinical models. This single-arm phase I clinical trial is in progress to assess the safety, feasibility, and immunogenicity of personalized neoantigen vaccines in combinationwith pembrolizumab in patients with advanced solid cancers. Methods: The vaccine consists of up to 20 peptides (15-30 mer) comprising patient-specific neoantigens identified from tumorDNA and mRNA sequencing data using REAL-neo and delivered with GM-CSF as an adjuvant.The first cohort of three patients will be treated at dose level 1 consisting of 4 or 5 peptides at 300mcg/peptide and GM-CSF 125 mcg per injection site in each of four limbs. After Cohort 1 isdeemed safe, the study will expand to cohort 2, when patients will be enrolled at the same dose level for vaccine plus Pembrolizumab 200 mg i.v. Neoantigen vaccine will be given via sub- cutaneous injection on days 1, 4, 8, 15, and 21 (cohorts 1 and 2) and weeks 5 and 8 (booster dosefor cohort 2 only). Cohort 1 has been completed without dose-limiting toxicity (DLT). Enroll-ment in Cohort 2 began in January 2024. AEs are assessed according to CTCAE v5. and safetyfindings are reviewed by data safety medical board (DSMB). Key eligibility criteria include 1)histologically confirmed locally advanced or metastatic solid malignancies and 2) cancerprogression after at least one line of the standard-of-care (SOC) systemic treatment. Forcohort 2, patients must be eligible to receive pembrolizumab per SOC or the treating physician ’s judgment. Clinical trial information: NCT05269381. Research Sponsor: Mayo Clinic.DEVELOPMENTAL THERAPEUTICS —IMMUNOTHERAPY Downloaded from ascopubs.org by 190.236.76.167 on December 10, 2024 from 190.236.076.167 Copyright © 2024 American Society of Clinical Oncology. All rights reserved.