ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients1, yet harbours mutation-derived T cell neoantigens that are suitable for vaccines 2,3. Here in a phase I trial of adjuvant autogene cevumeran, an individualized neoantigen vaccine based on uridine mRNA-lipoplex nanoparticles, we synthesized mRNA neoantigen vaccines in real time from surgically resected PDAC tumours. After surgery, we sequentially administered atezolizumab (an anti-PD-L1 immunotherapy), autogene cevumeran (a maximum of 20 neoantigens per patient) and a modified version of a four-drug chemotherapy regimen (mFOLFIRINOX, comprising folinic acid, fluorouracil, irinotecan and oxaliplatin). The end points included vaccine-induced neoantigen-specific T cells by high-threshold assays, 18-month recurrence-free survival and oncologic feasibility. We treated 16 patients with atezolizumab and autogene cevumeran, then 15 patients with mFOLFIRINOX. Autogene cevumeran was administered within 3 days of benchmarked times, was tolerable and induced de novo high-magnitude neoantigen-specific T cells in 8 out of 16 patients, with half targeting more than one vaccine neoantigen. Using a new mathematical strategy to track T cell clones (CloneTrack) and functional assays, we found that vaccine-expanded T cells comprised up to 10% of all blood T cells, re-expanded with a vaccine booster and included long-lived polyfunctional neoantigen-specific effector CD8+ T cells. At 18-month median follow-up, patients with vaccine-expanded T cells (responders) had a longer median recurrence-free survival (not reached) compared with patients without vaccine-expanded T cells (non-responders; 13.4 months, P = 0.003). Differences in the immune fitness of the patients did not confound this correlation, as responders and non-responders mounted equivalent immunity to a concurrent unrelated mRNA vaccine against SARS-CoV-2. Thus, adjuvant atezolizumab, autogene cevumeran and mFOLFIRINOX induces substantial T cell activity that may correlate with delayed PDAC recurrence.
Subject(s)
Antigens, Neoplasm , Cancer Vaccines , Carcinoma, Pancreatic Ductal , Lymphocyte Activation , Pancreatic Neoplasms , T-Lymphocytes , Humans , Adjuvants, Immunologic/therapeutic use , Antigens, Neoplasm/immunology , Cancer Vaccines/immunology , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/immunology , Carcinoma, Pancreatic Ductal/therapy , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , Immunotherapy , Lymphocyte Activation/immunology , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/therapy , T-Lymphocytes/cytology , T-Lymphocytes/immunologyABSTRACT
BACKGROUND: The COVID crisis hit during the interview season for the Complex General Surgical Oncology (CGSO) fellowship. With minimal time to adapt, all programs transitioned to virtual interviews. Here we describe the experience of both program directors (PDs) and candidates with virtual interviews, and provide guidelines for implementation based on the results. METHODS: Surveys regarding interview day specifics and perceptions were created for CGSO fellowship PDs and candidates. They were distributed at the conclusion of the season, prior to match. RESULTS: Thirty (94%) PDs and 64 (79%) candidates responded. Eighty-three% of PDs and 79% of candidates agreed or strongly agreed that they felt comfortable creating a rank list. If given the choice, 60% of PDs and 45% of candidates would choose virtual interviews over in-person interviews. The majority of candidates found PD overviews, fellows only sessions and pre-interview materials helpful. CONCLUSION: Overall, the majority of PDs and candidates felt comfortable creating a rank list; however, more PDs preferred virtual interviews for the future. Our results also confirm key components of a virtual interview day.