Neoadjuvant Selicrelumab, an Agonist CD40 Antibody, Induces Changes in the Tumor Microenvironment in Patients with Resectable Pancreatic Cancer

  • Clin Cancer Res. 2021 Aug 15;27(16):4574-4586. doi: 10.1158/1078-0432.CCR-21-1047.
Katelyn T Byrne   #  1  2 ,  Courtney B Betts   #  3  4 ,  Rosemarie Mick   #  1  5 ,  Shamilene Sivagnanam  3 ,  David L Bajor  6 ,  Daniel A Laheru  7 ,  E Gabriela Chiorean  8 ,  Mark H O'Hara  1 ,  Shannon M Liudahl  3 ,  Craig Newcomb  5 ,  Cécile Alanio  2  9 ,  Ana P Ferreira  3 ,  Byung S Park  4 ,  Takuya Ohtani  9 ,  Austin P Huffman  1 ,  Sara A Väyrynen  10 ,  Andressa Dias Costa  10 ,  Judith C Kaiser  11 ,  Andreanne M Lacroix  11 ,  Colleen Redlinger  1 ,  Martin Stern  12 ,  Jonathan A Nowak  13 ,  E John Wherry  1  2  9 ,  Martin A Cheever  11 ,  Brian M Wolpin  10 ,  Emma E Furth  1 ,  Elizabeth M Jaffee  6 ,  Lisa M Coussens  3  4 ,  Robert H Vonderheide  14  2
Affiliations
  • 1. Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 2. Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 3. Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, Oregon.
  • 4. Knight Cancer Institute, Oregon Health and Science University-Portland State University School of Public Health, Portland, Oregon.
  • 5. Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 6. Case Comprehensive Cancer Center, Cleveland, Ohio.
  • 7. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
  • 8. University of Washington School of Medicine, Fred Hutchinson Cancer Research Center, Seattle, Washington.
  • 9. Department of Systems Pharmacology and Translational Therapeutics, Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 10. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • 11. Fred Hutchinson Cancer Research Center, Seattle, Washington.
  • 12. Roche Pharma Research and Early Development, Roche Innovation Center, Zurich, Switzerland.
  • 13. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
  • 14. Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. [email protected].
  • # Contributed equally.
PMID: 34112709 DOI: 10.1158/1078-0432.CCR-21-1047
Abstract

Purpose: CD40 activation is a novel clinical opportunity for Cancer Immunotherapy. Despite numerous active clinical trials with agonistic CD40 monoclonal antibodies (mAb), biological effects and treatment-related modulation of the tumor microenvironment (TME) remain poorly understood.

Patients and methods: Here, we performed a neoadjuvant clinical trial of agonistic CD40 mAb (selicrelumab) administered intravenously with or without chemotherapy to 16 patients with resectable pancreatic ductal adenocarcinoma (PDAC) before surgery followed by Adjuvant chemotherapy and CD40 mAb.

Results: The toxicity profile was acceptable, and overall survival was 23.4 months (95% confidence interval, 18.0-28.8 months). Based on a novel multiplexed immunohistochemistry platform, we report evidence that neoadjuvant selicrelumab leads to major differences in the TME compared with resection specimens from treatment-naïve PDAC patients or patients given neoadjuvant chemotherapy/chemoradiotherapy only. For selicrelumab-treated tumors, 82% were T-cell enriched, compared with 37% of untreated tumors (P = 0.004) and 23% of chemotherapy/chemoradiation-treated tumors (P = 0.012). T cells in both the TME and circulation were more active and proliferative after selicrelumab. Tumor fibrosis was reduced, M2-like tumor-associated macrophages were fewer, and intratumoral dendritic cells were more mature. Inflammatory cytokines/sec CXCL10 and CCL22 increased systemically after selicrelumab.

Conclusions: This unparalleled examination of CD40 mAb therapeutic mechanisms in patients provides insights for design of subsequent clinical trials targeting CD40 in Cancer.

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