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 Journal Article
| Authors: | Heumann, T.; Judkins, C.; Li, K.; Lim, S. J.; Hoare, J.; Parkinson, R.; Cao, H.; Zhang, T.; Gai, J.; Celiker, B.; Zhu, Q.; McPhaul, T.; Durham, J.; Purtell, K.; Klein, R.; Laheru, D.; De Jesus-Acosta, A.; Le, D. T.; Narang, A.; Anders, R.; Burkhart, R.; Burns, W.; Soares, K.; Wolfgang, C.; Thompson, E.; Jaffee, E.; Wang, H.; He, J.; Zheng, L. |
| Article Title: | 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 |
| 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. © 2023, The Author(s). |
| Keywords: | adult; cancer survival; clinical article; controlled study; human cell; overall survival; fatigue; fluorouracil; diarrhea; drug efficacy; drug safety; capecitabine; gemcitabine; paclitaxel; cancer adjuvant therapy; cancer patient; disease free survival; neoadjuvant therapy; pancreatic neoplasms; antineoplastic agent; adenocarcinoma; cd8+ t lymphocyte; cancer immunotherapy; low drug dose; multiple cycle treatment; nausea; randomized controlled trial; vomiting; antineoplastic combined chemotherapy protocols; myalgia; cohort analysis; cyclophosphamide; pathology; irinotecan; abdominal pain; arthralgia; chill; dizziness; fever; injection site reaction; pancreas carcinoma; rash; alanine aminotransferase; aspartate aminotransferase; malaise; folinic acid; pancreas tumor; cancer immunization; vaccination; cytotoxic t lymphocyte; pancreas adenocarcinoma; pancreatectomy; colitis; dermatitis; headache; interleukin 17; tumor; oxaliplatin; injection site erythema; antibody; t lymphocyte activation; vaccine; hyperhidrosis; thyroid disease; drug; swelling; comparative effectiveness; clinical outcome; injection site pruritus; hypertransaminasemia; injection site induration; pancreatic carcinoma; combination drug therapy; nivolumab; cell component; urelumab; cancer; humans; human; male; female; article; induced response; presyncope; galgenprostucel l plus litgenprostucel l |
| Journal Title: | Nature Communications |
| Volume: | 14 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2023-06-20 |
| Start Page: | 3650 |
| Language: | English |
| DOI: | 10.1038/s41467-023-39196-9 |
| PUBMED: | 37339979 |
| PROVIDER: | scopus |
| PMCID: | PMC10281953 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
