A personal neoantigen vaccine, NEO-PV-01, with anti-PD1 induces broad de novo anti-tumor immunity in patients with metastatic melanoma, NSCLC, and bladder cancer

Abstract

Background: Neoantigens arise from DNA mutations in cancer cells and are critical targets for tumor-specific T cell responses. Adjuvant treatment with a personal neoantigen vaccine induced broad immune response in melanoma patients and suggested the potential for synergy with an immune checkpoint inhibitor (Ott et al, Nature2017). NEO-PV-01 is a personal neoantigen vaccine containing multiple peptide epitopes based on the genomic profile of each patient's tumor. We report the first clinical and immune data of NEO-PV-01 in combination with nivolumab for patients with metastatic cancer (ClinicalTrials.gov: NCT02897765). Methods: NT-001 is a single-arm, Phase 1b study of NEO-PV-01 with nivolumab in patients with advanced melanoma, non-small cell lung cancer, or transitional cell carcinoma of the bladder. NEO-PV-01 is designed for each patient using DNA and RNA sequencing from a recently biopsied tumor, selecting patient MHC class I- and II-restricted neoantigen epitopes, and designing and manufacturing up to 20 long peptides. Patients begin bi- weekly nivolumab at week 0. At week 12, NEO-PV-01 plus the immune adjuvant Poly-ICLC is administered subcutaneously in a prime-boost format. The primary endpoint of the study is safety; secondary endpoints include overall response rate (ORR), clinical benefit rate (CBR), and progression free survival (PFS). Comprehensive immune assessment before, during, and after therapy is performed for each patient. Results: Of 21 patients who received at least one vaccination by the time of data cutoff (15 NOV 2017), 14 have completed the full vaccination schedule (10 - Melanoma, 3 - Lung, 1 - Bladder). Vaccine-related adverse events were mild, including injection site reactions and flu-like symptoms, with no vaccine-related SAEs observed. In the first 14 patients who completed vaccination by the time of data cutoff, we observed 5 patients with partial response (PR), 5 with stable disease (SD), and 4 with progressive disease (PD) (2 of whom had progression prior to vaccination). Several patients with PR and SD had durable and evolving responses following vaccination. Across all three tumor types, neoantigen-specific and polyfunctional CD4 and CD8 T cell responses of effector memory and central memory phenotypes were predominantly observed following vaccination as measured by ELISPOT, MHC tetramer staining, and FACS. Epitope spreading (T cell responses to neoantigens not included in the vaccine but identified in the patient's tumor), was observed in 2 of 4 patients analyzed. Assessment of preand post-treatment tumor biopsies with repeat exome sequencing, gene expression, as well as immunohistochemistry and pathologic analysis will be presented. Conclusions: Treatment with NEO-PV-01 with nivolumab has demonstrated minimal toxicity and ongoing clinical activity. Further, NEO-PV-01 is immunogenic inducing broad De novo neoantigen-specific immune responses in patients with metastatic cancers.