Journal Article

A platform trial of neoadjuvant and adjuvant antitumor vaccination alone or in combination with PD-1 antagonist and CD137 agonist antibodies in patients with resectable pancreatic adenocarcinoma

Anders, Robert, Wolfgang, Christopher, Celiker, Betul, Cao, Haihui, Gai, Jessica, Zheng, Lei, Purtell, Katrina, Judkins, Carol, Jaffee, Elizabeth, Zhang, Tengyi, Thompson, Elizabeth, Narang, Amol, Hoare, Jessica, Heumann, Thatcher, Burkhart, Richard, Li, Keyu, Laheru, Daniel, Zhu, Qingfeng, De Jesus-Acosta, Ana, He, Jin, Burns, William, Durham, Jennifer, Lim, Su Jin, Le, Dung T., Soares, Kevin, Parkinson, Rose, McPhaul, Thomas, Klein, Rachel, Wang, Hao

2023

Overview

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. GM-CSF-secreting whole-cell cancer vaccine (GVAX) promotes T-cell response against a range of tumor associated antigens in patients with pancreatic adenocarcinoma (PDA). Here the authors report the results of the initial three treatment arms of a platform trial of neoadjuvant and adjuvant GVAX alone or in combination with PD-1 antagonist and CD137 agonist antibodies in patients with resectable PDA.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/51 / 692/4028/67/1059/2325 / 692/4028/67/1059/4042 / 692/4028/67/1504/1713 / Adenocarcinoma / Adenocarcinoma - drug therapy / Agonists / Antibodies / Antigen (tumor-associated) / Antigens / Antineoplastic Combined Chemotherapy Protocols / Cancer / Cancer vaccines / CD137 antigen / CD8 antigen / Cyclophosphamide / Cytotoxicity / Granulocyte-macrophage colony-stimulating factor / Health services / Humanities and Social Sciences / Humans / Immunotherapy / Lymphocytes / Lymphocytes T / Monoclonal antibodies / multidisciplinary / Neoadjuvant Therapy - adverse effects / Nivolumab - therapeutic use / Pancreatic cancer / Pancreatic Neoplasms - drug therapy / Pancreatic Neoplasms - pathology / Patients / PD-1 protein / Science / Science (multidisciplinary) / Statistical analysis / Survival / Vaccination / Vaccines