Overcoming Immunological Resistance Enhances the Efficacy of A Novel Anti-tMUC1-CAR T Cell Treatment against Pancreatic Ductal Adenocarcinoma

Mahboubeh Yazdanifar, Ru Zhou, Priyanka Grover, Chandra Williams, Mukulika Bose, Laura J. Moore, Shu Ta Wu, John Maher, Didier Dreau, And Pinku Mukherjee

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)

Abstract

Chimeric antigen receptor (CAR) T cells have shown remarkable success in treating hematologic cancers. However, this efficacy has yet to translate to treatment in solid tumors. Pancreatic ductal adenocarcinoma (PDA) is a fatal malignancy with poor prognosis and limited treatment options. We have developed a second generation CAR T cell using the variable fragments of a novel monoclonal antibody, TAB004, which specifically binds the tumor-associated-MUC1 (tMUC1). tMUC1 is overexpressed on ~85% of all human PDA. We present data showing that TAB004-derived CAR T cells specifically bind to tMUC1 on PDA cells and show robust killing activity; however, they do not bind or kill normal epithelial cells. We further demonstrated that the tMUC1-CAR T cells control the growth of orthotopic pancreatic tumors in vivo. We witnessed that some PDA cells (HPAFII and CFPAC) were refractory to CAR T cell treatment. qPCR analysis of several genes revealed overexpression of indoleamine 2, 3-dioxygenases-1 (IDO1), cyclooxygenase 1 and 2 (COX1/2), and galectin-9 (Gal-9) in resistant PDA cells. We showed that combination of CAR T cells and biological inhibitors of IDO1, COX1/2, and Gal-9 resulted in significant enhancement of CAR T cell cytotoxicity against PDA cells. Overcoming PDA resistance is a significant advancement in the field.

Original languageEnglish
JournalCells
Volume8
Issue number9
DOIs
Publication statusPublished - 11 Sept 2019

Keywords

  • CAR T cell
  • engineered T cell
  • Immunotherapy
  • MUC1
  • pancreatic cancer
  • pancreatic ductal adenocarcinoma
  • resistance
  • targeted therapy

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