CD40 Agonist Antibodies in Cancer Immunotherapy

Annu Rev Med. 2020 Jan 27;71:47-58. doi: 10.1146/annurev-med-062518-045435. Epub 2019 Aug 14.


CD40 is a cell-surface member of the TNF (tumor necrosis factor) receptor superfamily. Upon activation, CD40 can license dendritic cells to promote antitumor T cell activation and re-educate macrophages to destroy tumor stroma. Numerous agonist CD40 antibodies of varying formulations have been evaluated in the clinic and found to be tolerable and feasible. Administration is associated with mild to moderate (but transient) cytokine release syndrome, readily managed in the outpatient setting. Antitumor activity with or without anti-CTLA4 monoclonal antibody (mAb) therapy has been observed in patients with melanoma, and major tumor regressions have been observed in patients with pancreatic cancer, mesothelioma, and other tumors in combination with chemotherapy. In a recent study of chemotherapy plus CD40 mAb, with or without PD-1 mAb, the objective response rate in patients with untreated, metastatic pancreatic cancer was >50%. Mechanistically, the combination of chemotherapy followed by CD40 mAb functions as an in situ vaccine; in addition, destruction of stroma by CD40-activated macrophages may enhance chemotherapy delivery. Evidence to date suggests that CD40 activation is a critical and nonredundant mechanism to convert so-called cold tumors to hot ones (with prominent tumor infiltration of T cells), sensitizing them to checkpoint inhibition.

Keywords: CD40; cancer; immunotherapy; pancreatic cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antibodies, Monoclonal / therapeutic use*
  • CD40 Antigens / antagonists & inhibitors*
  • CD40 Antigens / immunology*
  • Disease-Free Survival
  • Humans
  • Immunotherapy / methods*
  • Lymphocyte Activation / immunology
  • Melanoma / mortality
  • Melanoma / pathology
  • Melanoma / therapy*
  • Mice
  • Pancreatic Neoplasms / mortality
  • Pancreatic Neoplasms / pathology
  • Pancreatic Neoplasms / therapy
  • Prognosis
  • Risk Assessment
  • Skin Neoplasms / mortality
  • Skin Neoplasms / pathology
  • Skin Neoplasms / therapy*
  • Survival Rate
  • Treatment Outcome


  • Antibodies, Monoclonal
  • CD40 Antigens