Overcoming Immunological Resistance Enhances the Efficacy of a Novel anti-tMUC1 CAR T Cell Treatment Against Pancreatic Ductal Adenocarcinoma

Yazdanifar, M.; Zhou, R.; Grover, P.; Williams, C.; Bose, M.; Moore, L. J.; Wu, S.-t.; Chi, R.; Maher, J.; Dreau, D.; Mukherjee, P.

doi:10.1101/642934

bioRxiv · 10.1101/642934

Overcoming Immunological Resistance Enhances the Efficacy of a Novel anti-tMUC1 CAR T Cell Treatment Against Pancreatic Ductal Adenocarcinoma

Yazdanifar, M.·Zhou, R.·Grover, P.·Williams, C.·Bose, M.·Moore, L. J.·Wu, S.-t.·Chi, R.·Maher, J.·Dreau, D.·Mukherjee, P.

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Abstract

Chimeric antigen receptor engineered T cells (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. Treatment options are limited and commonly associated with severe side effects. We have developed and characterized a second generation CAR engineered T cell using the light and heavy chain sequence derived from a novel monoclonal antibody, TAB004, that specifically binds the tumor associated antigen, tMUC1. tMUC1 is overexpressed in varying levels on ~85% of all human PDA. We present data showing that the TAB004 derived CAR T cells (tMUC1-CAR T cells) specifically bind to tMUC1 on PDA cells and is cytotoxic against the majority of the PDA cell lines. The tMUC1-CAR T cells do not bind or kill normal epithelial cells. We further demonstrate that the tMUC1-CAR T cells control the growth of orthotopic pancreatic tumors in vivo. PDAs are generally cold tumors with resistance to many standard treatment modalities, thus, it was not surprising that some of the PDA cell lines were refractory to CAR T cell treatment. qPCR analysis of several genes known to be associated with immune resistance revealed overexpression of indoleamine 2, 3-dioxygenases-1 (IDO1), Cyclooxygenase 1 and 2 (COX1 and COX2), Adenosine deaminases acting on RNA (ADAR1) and galectin-9 (Gal-9). We treated resistant PDA cells with a combination of CAR T cells and biological inhibitors of IDO1, COX1/2, ADAR1, and Gal-9. Results showed a significant enhancement of CAR T cell cytotoxicity against PDA cells when inhibiting IDO1, COX1/2, and Gal-9 but not ADAR1 or COX2. Overcoming CAR T cell resistance in PDA is a significant advancement in the field and may lead to future combination therapies that are less toxic but more efficient against this deadly disease.

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Yazdanifar, M., Zhou, R., Grover, P., Williams, C., Bose, M., Moore, L. J., Wu, S.-t., Chi, R., Maher, J., Dreau, D., Mukherjee, P.. 2019-05-20. Overcoming Immunological Resistance Enhances the Efficacy of a Novel anti-tMUC1 CAR T Cell Treatment Against Pancreatic Ductal Adenocarcinoma. https://doi.org/10.1101/642934

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