Academia Meets Industry at the Multimedia Grand Challenge

This column is about last year's ACM Multimedia Grand Challenge in Florence, Italy, an event that endeavors to connect (academic) researchers more effectively with the realities of the business world. The authors describe the 10 challenges and present the three winning applications

Penetrating neck injury in an isolated medical setting

Graham M Slaney, Anthony Guiney, Yvonne Hezel, Philip Weinstei

A Histone Deacetylase Inhibitor, Panobinostat, Enhances Chimeric Antigen Receptor T-cell Antitumor Effect Against Pancreatic Cancer

Abstract Purpose: In this article, we describe a combination chimeric antigen receptor (CAR) T-cell therapy that eradicated the majority of tumors in two immunocompetent murine pancreatic cancer models and a human pancreatic cancer xenograft model. Experimental Design: We used a dual-specific murine CAR T cell that expresses a CAR against the Her2 tumor antigen, and a T-cell receptor (TCR) specific for gp100. As gp100 is also known as pMEL, the dual-specific CAR T cells are thus denoted as CARaMEL cells. A vaccine containing live vaccinia virus coding a gp100 minigene (VV-gp100) was administered to the recipient mice to stimulate CARaMEL cells. The treatment also included the histone deacetylase inhibitor panobinostat (Pano). Results: The combination treatment enabled significant suppression of Her2+ pancreatic cancers leading to the eradication of the majority of the tumors. Besides inducing cancer cell apoptosis, Pano enhanced CAR T-cell gene accessibility and promoted CAR T-cell differentiation into central memory cells. To test the translational potential of this approach, we established a method to transduce human T cells with an anti-Her2 CAR and a gp100-TCR. The exposure of the human T cells to Pano promoted a T-cell central memory phenotype and the combination treatment of human CARaMEL cells and Pano eradicated human pancreatic cancer xenografts in mice. Conclusions: We propose that patients with pancreatic cancer could be treated using a scheme that contains dual-specific CAR T cells, a vaccine that activates the dual-specific CAR T cells through their TCR, and the administration of Pano. </jats:sec

Supplementary Figure 2 from A Histone Deacetylase Inhibitor, Panobinostat, Enhances Chimeric Antigen Receptor T-cell Antitumor Effect Against Pancreatic Cancer

Supplementary Figure 2. Pancreatic cells are resistant to VV-gp100 oncolysis but sensitive to CAR T cell-mediated cytotoxicity.</p

Supplementary Figure 6 from A Histone Deacetylase Inhibitor, Panobinostat, Enhances Chimeric Antigen Receptor T-cell Antitumor Effect Against Pancreatic Cancer

Supplementary Figure 6. The infiltration of CD8+ cells to the Her2+ non-tumor regions.</p

Supplementary Figure 5 from A Histone Deacetylase Inhibitor, Panobinostat, Enhances Chimeric Antigen Receptor T-cell Antitumor Effect Against Pancreatic Cancer

Supplementary Figure 5. Pano did not alter Her2 or H2-Db expression on Panc02-Her2 tumor cells in vivo and CARaMEL cells were detectable over 100 days in ACTIV+ Pano treated mice.</p

Supplementary Figure 3 from A Histone Deacetylase Inhibitor, Panobinostat, Enhances Chimeric Antigen Receptor T-cell Antitumor Effect Against Pancreatic Cancer

Supplementary Figure 3. Pano induced pancreatic tumor cell apoptosis.</p

Supplementary Figure 1 from A Histone Deacetylase Inhibitor, Panobinostat, Enhances Chimeric Antigen Receptor T-cell Antitumor Effect Against Pancreatic Cancer

Supplementary Figure 1. Panc02-Her2, KPC-Her2 and 24JK-Her2 cells express comparable levels of Her2.</p

Supplementary Figure 8 from A Histone Deacetylase Inhibitor, Panobinostat, Enhances Chimeric Antigen Receptor T-cell Antitumor Effect Against Pancreatic Cancer

Supplementary Figure 8. Proposed mechanisms and clinical application for the ACTIV+Pano treatment.</p