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

Thatcher Heumann, Carol Judkins, Keyu Li, Su Jin Lim, Jessica Hoare, Rose Parkinson, Haihui Cao, Tengyi Zhang, Jessica Gai, Betul Celiker, Qingfeng Zhu, Thomas McPhaul, Jennifer Durham, Katrina Purtell, Rachel Klein, Daniel Laheru, Ana De Jesus-Acosta, Dung T. Le, Amol Narang, Robert Anders, Richard Burkhart, William Burns, Kevin Soares, Christopher Wolfgang, Elizabeth Thompson, Elizabeth Jaffee, Hao Wang, Jin He and Lei Zheng ()
Additional contact information
Thatcher Heumann: Johns Hopkins University School of Medicine
Carol Judkins: Johns Hopkins University School of Medicine
Keyu Li: West China Hospital, Sichuan University
Su Jin Lim: Johns Hopkins University School of Medicine
Jessica Hoare: Johns Hopkins University School of Medicine
Rose Parkinson: Johns Hopkins University School of Medicine
Haihui Cao: Johns Hopkins University School of Medicine
Tengyi Zhang: Johns Hopkins University School of Medicine
Jessica Gai: Johns Hopkins University School of Medicine
Betul Celiker: Johns Hopkins University School of Medicine
Qingfeng Zhu: Johns Hopkins University School of Medicine
Thomas McPhaul: Johns Hopkins University School of Medicine
Jennifer Durham: Johns Hopkins University School of Medicine
Katrina Purtell: Johns Hopkins University School of Medicine
Rachel Klein: Johns Hopkins University School of Medicine
Daniel Laheru: Johns Hopkins University School of Medicine
Ana De Jesus-Acosta: Johns Hopkins University School of Medicine
Dung T. Le: Johns Hopkins University School of Medicine
Amol Narang: Johns Hopkins University School of Medicine
Robert Anders: Johns Hopkins University School of Medicine
Richard Burkhart: Johns Hopkins University School of Medicine
William Burns: Johns Hopkins University School of Medicine
Kevin Soares: Memorial Sloan Kettering Cancer Center
Christopher Wolfgang: New York University School of Medicine and NYU-Langone Medical Center
Elizabeth Thompson: Johns Hopkins University School of Medicine
Elizabeth Jaffee: Johns Hopkins University School of Medicine
Hao Wang: Johns Hopkins University School of Medicine
Jin He: Johns Hopkins University School of Medicine
Lei Zheng: Johns Hopkins University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39196-9

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