Adjuvant personalized multivalent neoantigen DNA vaccination for MGMT unmethylated glioblastoma: a phase 1 trial
(1) Garfinkle EAR (2) Perales-Linares R (3) Gimple RC (4) Livingstone AJ (5) Roberts KF (6) Butt OH (7) Goedegebuure SP (8) McLellan MD (9) Chang GS (10) Hundal J (11) Yan J (12) Navarro JB (13) Paxton SA (14) Chattopadhyay S (15) Cooch N (16) Perales-Puchalt A (17) Stavroulaki K (18) Rochestie S (19) Peters J (20) Junker B (21) Campian JL (22) Chheda MG (23) Chicoine MR (24) Kim AH (25) Willie JT (26) Zipfel GJ (27) Dowling JL (28) Miller CA (29) Griffith OL (30) Griffith M (31) Gillanders WE (32) Miller KE (33) Mardis ER (34) Sardesai NY (35) Dunn GP (36) Johanns TM
In a phase 1 study, Garfinkle et al. vaccinated 9 patients with MGMT unmethylated glioblastoma with a personalized DNA-based vaccine following surgical resection and radiation. GNOS-PVO1 encoded up to 40 neoantigens identified from 3–4 distinct tumor regions per patient, and was well tolerated. The median 24-month survival rate was 33%, including a patient who remained disease-free over 4 years after diagnosis. Survival correlated with increases in peripheral CD8+CD69+ and CD8+IFNγ+ T cells. Increased tumor-infiltrating CD8+ T cells, with expanded de novo and pre-existing TCR clonotypes in the tumor and blood, were observed upon vaccination.
Contributed by Ute Burkhardt
(1) Garfinkle EAR (2) Perales-Linares R (3) Gimple RC (4) Livingstone AJ (5) Roberts KF (6) Butt OH (7) Goedegebuure SP (8) McLellan MD (9) Chang GS (10) Hundal J (11) Yan J (12) Navarro JB (13) Paxton SA (14) Chattopadhyay S (15) Cooch N (16) Perales-Puchalt A (17) Stavroulaki K (18) Rochestie S (19) Peters J (20) Junker B (21) Campian JL (22) Chheda MG (23) Chicoine MR (24) Kim AH (25) Willie JT (26) Zipfel GJ (27) Dowling JL (28) Miller CA (29) Griffith OL (30) Griffith M (31) Gillanders WE (32) Miller KE (33) Mardis ER (34) Sardesai NY (35) Dunn GP (36) Johanns TM
In a phase 1 study, Garfinkle et al. vaccinated 9 patients with MGMT unmethylated glioblastoma with a personalized DNA-based vaccine following surgical resection and radiation. GNOS-PVO1 encoded up to 40 neoantigens identified from 3–4 distinct tumor regions per patient, and was well tolerated. The median 24-month survival rate was 33%, including a patient who remained disease-free over 4 years after diagnosis. Survival correlated with increases in peripheral CD8+CD69+ and CD8+IFNγ+ T cells. Increased tumor-infiltrating CD8+ T cells, with expanded de novo and pre-existing TCR clonotypes in the tumor and blood, were observed upon vaccination.
Contributed by Ute Burkhardt
ABSTRACT: Glioblastoma is a fatal disease with a median prognosis of 12-18_months. Recent studies have shown encouraging results using neoantigen-based vaccines to stimulate glioblastoma-directed immune responses, but overall immunogenicity has been low. Here, we report the results of an open-label, single-arm, phase 1 clinical trial (GT-20) to evaluate the safety and feasibility (primary endpoints) as well as immunogenicity and preliminary clinical activity (secondary endpoints) of GNOS-PV01 monotherapy, a DNA-based personalized therapeutic cancer vaccine administered following surgical resection and radiation for patients with MGMT unmethylated glioblastoma. The GT-20 study vaccinated nine patients, using up to 40 neoantigens per patient (range, 17-40) without causing any serious adverse events, unexpected toxicities or dose-limiting toxicities. The vaccine induced activation and expansion of circulating peripheral T_cells in all evaluated patients, except one who was being treated with dexamethasone. The secondary endpoint was to evaluate 6_month progression-free survival and 12_month overall survival; each observed in 66.7% of patients. Median progression-free survival was 8.5_months, median overall survival was 16.3_months and survival at 24_months was 33%, including one long-term survivor still alive 4_years from the time of initial surgery. This study met the pre-specified endpoints and supports the use of GNOS-PV01 as a potentially impactful component of glioblastoma immunotherapy. ClinicalTrials.gov: NCT04015700 .
Author Info:
(1) The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA. (2) Geneos Therapeutics, Philadelphia, PA, USA. (3) Department
of Medicine, Washington University School of Medicine, St. Louis, MO, USA. (4) Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, USA. (5) Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. (6) Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, USA. The Brain Tumor Center at Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO, USA. (7) The Brain Tumor Center at Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO, USA. Department of Surgery, Washington University in St. Louis, St. Louis, MO, USA. (8) McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA. (9) McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA. (10) McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA. (11) Geneos Therapeutics, Philadelphia, PA, USA. (12) The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA. (13) The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA. Biomedical Sciences Graduate Program, The Ohio State University College of Medicine, Columbus, OH, USA. (14) The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA. The Ohio State University, Columbus, OH, USA. (15) Geneos Therapeutics, Philadelphia, PA, USA. (16) Geneos Therapeutics, Philadelphia, PA, USA. (17) Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA. (18) Geneos Therapeutics, Philadelphia, PA, USA. (19) Geneos Therapeutics, Philadelphia, PA, USA. (20) BioProcess Advantage LLC, Westfield, NJ, USA. (21) Department of Neurology, Mayo Clinic, Rochester, MN, USA. (22) Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. The Brain Tumor Center at Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO, USA. (23) Department of Neurosurgery, University of Missouri, Columbia, MO, USA. (24) The Brain Tumor Center at Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO, USA. Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, USA. (25) Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, USA. (26) The Brain Tumor Center at Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO, USA. Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, USA. (27) The Brain Tumor Center at Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO, USA. Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, USA. (28) Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA. Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA. (29) Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA. Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA. (30) Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA. Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA. (31) Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA. (32) The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA. Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA. (33) The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA. Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA. (34) Geneos Therapeutics, Philadelphia, PA, USA. (35) Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. (36) Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, USA. tannerjohanns@wustl.edu. The Brain Tumor Center at Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO, USA. tannerjohanns@wustl.edu. Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Program, Washington University School of Medicine, St. Louis, MO, USA. tannerjohanns@wustl.edu.
