Barbara Franziska Schorg
Eberhard Karls University, Germany
Title: Highly efficient treatment of progressed cancer: combining tumor antigen (TA)-specific Th1-cells with immune checkpoint blockade
Biography
Biography: Barbara Franziska Schorg
Abstract
Tumor cells and immune cells express inhibitory immune-checkpoint (ICP) ligands that paralyze tumor infiltrating T-cells. ICP-specific antibodies can restore T-cell-functions. Moreover, tumor-antigen (TA)-specific IFN-y secreting CD4+ T-cells (Th1) mediate strong anti-tumoral effects and can induce senescence in cancer cells. Thus, we establish a highly efficient TA-Th1-cell and checkpoint inhibitor based combined immunotherapy (CIT) in RIP1-Tag2 (RT2) mice with advanced endogenous pancreatic insular cell carcinomas where ICP-blockade and TA-Th1-cells alone are not sufficient. We started our CIT in 10-11 weeks old RT2-mice which usually die with 14 weeks. At this stage BGL are reduced due to enhanced insulin secretion. Mice underwent a single 2Gy whole body radiation followed by repeated injections of TA-Th1-cells (1x weekly) and of LAG-3+PD-L1-mAbs (1-2x weekly) or isotype-Abs. During CIT-treatment, the median BGL of RT2-mice increased from 80 mg/dl to nearly normal values of 91 mg/dl (week 14, n=30, p<0.01) while the BGL of RT2-mice treated with TA-Th1-cells+isotype mAbs already dropped to 66 mg/dl (n=30). Treated with LAG-3+PD-L1-mAbs alone was inefficient (week 14: ï¾40 mg/dl, n=23). CIT-treatment extended the lifespan of the CIT-treated RT2-mice from 14 to 21 weeks. CIT-treated RT2-mice revealed very small tumors and a strong lymphocytic infiltrate. In contrast, LAG-3+PD-L1-mAbs treated RT2-mice exhibited large, vascularized endocrine tumors with a slight lymphcytic infiltrate. Insular cell carcinomas of CIT-treated RT2-mice revealed high p16 and low Ki67 expression but opposite results in the control groups. Thus, our CIT is applicable to reinforce Th1-cell based immunotherapies and to induce carcinoma regression even in mice with progressed carcinomas.