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

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.

Mechanisms of T-Cell Exhaustion in Pancreatic Cancer

“…Finally, the role of the Gal9, expressed in both leukocytes and tumor cells in PDAC, has been shown. The blockade of Gal9/Dectin-1 interaction improved intratumoral T-cell activation in PDAC and associated with TAM reprogramming, while only Gal9 inhibition enhanced CAR-T-cell cytotoxicity and alleviated PDAC immunotherapy resistance [ 120 , 121 ]. Gal9 interaction with co-inhibitory receptor TIM-3 on Teff, Th, and innate immune cells induce dysfunctional programming in T-cells in chronic infection [ 122 ].…”

The Galectin Family as Molecular Targets: Hopes for Defeating Pancreatic Cancer

“…Gal9 inhibition is also associated with immunogenic reprogramming of tumor-associated macrophages (TAMs) in PDA ( Figure 1, Table 1) [40]. Finally, Gal9 is involved in PDA immunotherapy resistance, with recent data showing that Gal9 inhibition enhances chimeric antigen receptor (CAR) T-cell cytotoxicity [94] (Table 1).…”

Counteracting CAR T cell dysfunction

“…As that the precise mechanisms by which TIM-3 and LAG-3 induce T cell exhaustion and senescence are still not fully understood, only a few studies have explored selective blockade of these inhibitory receptors in CAR T cells. In one effort, antibody-based blocking of Galectin-9, a putative TIM-3 ligand, reduced exhaustion of CAR T cells and significantly increased their cytotoxicity against previously resistant tumor cells [37]. Of note, FGL1 has been identified as a major ligand for LAG-3, and possibly will be considered as a candidate target for LAG-3 signaling blockade in the future studies [38].…”