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

• Published in: Nature communications Vol. 14; no. 1; p. 3650
• Main Authors: Heumann, Thatcher, Judkins, Carol, Li, Keyu, Lim, Su Jin, Hoare, Jessica, Parkinson, Rose, Cao, Haihui, Zhang, Tengyi, Gai, Jessica, Celiker, Betul, Zhu, Qingfeng, McPhaul, Thomas, Durham, Jennifer, Purtell, Katrina, Klein, Rachel, Laheru, Daniel, De Jesus-Acosta, Ana, Le, Dung T., Narang, Amol, Anders, Robert, Burkhart, Richard, Burns, William, Soares, Kevin, Wolfgang, Christopher, Thompson, Elizabeth, Jaffee, Elizabeth, Wang, Hao, He, Jin, Zheng, Lei
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.06.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 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; 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
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-39196-9

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.