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

Yazdanifar Yazdanifar,Mukherjee Mukherjee,Williams Williams,Wu Wu,Dreau Dreau,Maher Maher,Zhou Zhou,Grover Grover,Moore Moore,Bose Bose

doi:10.3390/cells8091070

Yazdanifar Yazdanifar, Mukherjee Mukherjee + Show 8 more

Open Access

https://doi.org/10.3390/cells8091070

Copy DOI

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.

Highlights

Pancreatic ductal adenocarcinoma (PDA), which arises from exocrine cells of the pancreas [1], is one of the deadliest forms of cancer with a mortality rate closely parallel to incidence [2]
Chimeric antigen receptor (CAR) T cell therapy has shown enormous success in treating hematologic malignancies [6,7] and metastatic melanoma [8]; this success has not been extended to adenocarcinomas [9]
We introduce a novel anti-tMUC1-CAR T cell using scFv derived from a highly specific anti-tMUC1 monoclonal Ab, TAB004, that does not recognize the normal form of MUC1 [21,22]

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDA), which arises from exocrine cells of the pancreas [1], is one of the deadliest forms of cancer with a mortality rate closely parallel to incidence [2] It is the third leading cause of cancer related deaths in the United States, yet treatment options are limited and often associated with a high recurrence rate and poor prognosis [3]. CAR T cell therapy has shown enormous success in treating hematologic malignancies [6,7] and metastatic melanoma [8]; this success has not been extended to adenocarcinomas [9] This may be due to the limited selection of antigens that are expressed at a high level on the surface of solid tumors

Methods

Results

Conclusion