In an extended follow-up (median 3.2-year) on a phase 1 trial in which 16 patients with PDAC were treated with surgery, anti-PD-L1, autogene cevumeran (individualized mRNA-based neoantigen vaccine), and chemotherapy, responders (n=8) with vaccine-induced T cells showed prolonged RFS (not reached) compared to non-responders without them (13.4 months). In responders, 86% of induced clones persisted at substantial frequencies ~3 years post-vaccination. Vaccine-induced CD8+ T cells had an average estimated lifespan of 7.7 years, with ~20% of clones expected to last for multiple decades, assuming cytotoxic, tissue-resident memory-like states.
Contributed by Lauren Hitchings
ABSTRACT: A fundamental challenge for cancer vaccines is to generate long-lived functional T cells that are specific for tumour antigens. Here we find that mRNA-lipoplex vaccines against somatic mutation-derived neoantigens may solve this challenge in pancreatic ductal adenocarcinoma (PDAC), a lethal cancer with few mutations. At an extended 3.2-year median follow-up from a phase 1 trial of surgery, atezolizumab (PD-L1 inhibitory antibody), autogene cevumeran1 (individualized neoantigen vaccine with backbone-optimized uridine mRNA-lipoplex nanoparticles) and modified (m) FOLFIRINOX (chemotherapy) in patients with PDAC, we find that responders with vaccine-induced T cells (n = 8) have prolonged recurrence-free survival (RFS; median not reached) compared with non-responders without vaccine-induced T cells (n = 8; median RFS 13.4 months; P = 0.007). In responders, autogene cevumeran induces CD8+ T cell clones with an average estimated lifespan of 7.7 years (range 1.5 to roughly 100 years), with approximately 20% of clones having latent multi-decade lifespans that may outlive hosts. Eighty-six percent of clones per patient persist at substantial frequencies approximately 3 years post-vaccination, including clones with high avidity to PDAC neoepitopes. Using PhenoTrack, a novel computational strategy to trace single T cell phenotypes, we uncover that vaccine-induced clones are undetectable in pre-vaccination tissues, and assume a cytotoxic, tissue-resident memory-like T cell state up to three years post-vaccination with preserved neoantigen-specific effector function. Two responders recurred and evidenced fewer vaccine-induced T cells. Furthermore, recurrent PDACs were pruned of vaccine-targeted cancer clones. Thus, in PDAC, autogene cevumeran induces de novo CD8+ T cells with multiyear longevity, substantial magnitude and durable effector functions that may delay PDAC recurrence. Adjuvant mRNA-lipoplex neoantigen vaccines may thus solve a pivotal obstacle for cancer vaccination.
Author Info: (1) Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Hepatopancreatobiliary Service, Department of Surge
Author Info: (1) Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. The Olayan Center for Cancer Vaccines, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Computational Oncology Service, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (2) Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (3) Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (4) Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Computational Oncology Service, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (5) Computational Oncology Service, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (6) The Olayan Center for Cancer Vaccines, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (7) The Olayan Center for Cancer Vaccines, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Computational Oncology Service, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (8) Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (9) Computational Oncology Service, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (10) Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (11) Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (12) Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (13) Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (14) Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (15) Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (16) Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (17) Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 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(28) Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (29) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (30) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (31) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (32) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (33) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (34) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (35) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (36) Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (37) Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (38) Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (39) Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (40) Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (41) Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (42) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (43) Genentech, San Francisco, CA, USA. (44) BioNTech, Mainz, Germany. HI-TRON, Helmholtz Institute for Translational Oncology, Mainz, Germany. (45) BioNTech, Mainz, Germany. HI-TRON, Helmholtz Institute for Translational Oncology, Mainz, Germany. (46) The Olayan Center for Cancer Vaccines, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Computational Oncology Service, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, Weill Cornell Medical College, New York, NY, USA. (47) Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. balachav@mskcc.org. Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. balachav@mskcc.org. The Olayan Center for Cancer Vaccines, Memorial Sloan Kettering Cancer Center, New York, NY, USA. balachav@mskcc.org. David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA. balachav@mskcc.org.
