Based on analysis of resected tumors after neoadjuvant vaccination with GVAX (allogeneic GM-CSF-secreting whole-cell pancreatic cancer vaccine) + low-dose cyclophosphamide (cy-GVAX; arm A) or cy-GVAX + nivolumab (arm B), Heumann et al. added a CD137 agonist, urelumab (arm C). The post-treatment density of CD8+CD137+ TILs within tertiary lymphoid aggregates in the TME was significantly higher in Arm C than in arms A or B. Arm C showed a numerical improvement in disease-free and overall survival compared to arms A and B; no differences were detected between arms A and B.
Contributed by Maartje Wouters
ABSTRACT: A neoadjuvant immunotherapy platform clinical trial allows for rapid evaluation of treatment-related changes in tumors and identifying targets to optimize treatment responses. We enrolled patients with resectable pancreatic adenocarcinoma into such a platform trial (NCT02451982) to receive pancreatic cancer GVAX vaccine with low-dose cyclophosphamide alone (Arm A; n = 16), with anti-PD-1 antibody nivolumab (Arm B; n = 14), and with both nivolumab and anti-CD137 agonist antibody urelumab (Arm C; n = 10), respectively. The primary endpoint for Arms A/B - treatment-related change in IL17A expression in vaccine-induced lymphoid aggregates - was previously published. Here, we report the primary endpoint for Arms B/C: treatment-related change in intratumoral CD8+ CD137+ cells and the secondary outcomes including safety, disease-free and overall survivals for all Arms. Treatment with GVAX+nivolumab+urelumab meets the primary endpoint by significantly increasing intratumoral CD8+ CD137+ cells (p = 0.003) compared to GVAX+Nivolumab. All treatments are well-tolerated. Median disease-free and overall survivals, respectively, are 13.90/14.98/33.51 and 23.59/27.01/35.55 months for Arms A/B/C. GVAX+nivolumab+urelumab demonstrates numerically-improved disease-free survival (HR = 0.55, p = 0.242; HR = 0.51, p = 0.173) and overall survival (HR = 0.59, p = 0.377; HR = 0.53, p = 0.279) compared to GVAX and GVAX+nivolumab, respectively, although not statistically significant due to small sample size. Therefore, neoadjuvant and adjuvant GVAX with PD-1 blockade and CD137 agonist antibody therapy is safe, increases intratumoral activated, cytotoxic T cells, and demonstrates a potentially promising efficacy signal in resectable pancreatic adenocarcinoma that warrants further study.
Author Info: (1) The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Jo
Author Info: (1) The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Vanderbilt University Medical Center, Department of Hematology-Oncology, Nashville, TN, USA. The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA. (2) The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA. (3) Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China. (4) The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Division of Quantitative Sciences, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (5) The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA. (6) The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA. (7) The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA. (8) The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program at Johns Hopkins, Baltimore, MD, USA. (9) The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program at Johns Hopkins, Baltimore, MD, USA. (10) The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA. (11) The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program at Johns Hopkins, Baltimore, MD, USA. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (12) The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program at Johns Hopkins, Baltimore, MD, USA. Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (13) The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA. (14) The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA. (15) The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (16) The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program at Johns Hopkins, Baltimore, MD, USA. (17) The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program at Johns Hopkins, Baltimore, MD, USA. (18) The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program at Johns Hopkins, Baltimore, MD, USA. (19) The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program at Johns Hopkins, Baltimore, MD, USA. Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (20) The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program at Johns Hopkins, Baltimore, MD, USA. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (21) The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program at Johns Hopkins, Baltimore, MD, USA. Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (22) The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program at Johns Hopkins, Baltimore, MD, USA. Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (23) Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (24) Department of Surgery, New York University School of Medicine and NYU-Langone Medical Center, New York, NY, USA. (25) The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program at Johns Hopkins, Baltimore, MD, USA. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (26) The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program at Johns Hopkins, Baltimore, MD, USA. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (27) The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA. Division of Quantitative Sciences, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (28) The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program at Johns Hopkins, Baltimore, MD, USA. Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (29) The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. lzheng6@jhmi.edu. The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA. lzheng6@jhmi.edu. The Pancreatic Cancer Precision Medicine Center of Excellence Program at Johns Hopkins, Baltimore, MD, USA. lzheng6@jhmi.edu. Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. lzheng6@jhmi.edu.
