Josephine F Trott1, Omran Abu Aboud1, Bridget McLaughlin2, Katie L Anderson3,4,5,6, Jaime F Modiano3,4,5,6,7, Kyoungmi Kim8, Kuang-Yu Jen9, William Senapedis10, Hua Chang10, Yosef Landesman10, Erkan Baloglu10, Roberto Pili11, Robert H Weiss1,2,12. 1. Division of Nephrology, Department of Internal Medicine, University of California, Davis, California. 2. Comprehensive Cancer Center, University of California, Davis, California. 3. Animal Cancer Care and Research Program, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota. 4. Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota. 5. Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. 6. Center for Immunology, University of Minnesota, Minneapolis, Minnesota. 7. Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota. 8. Division of Biostatistics, Department of Public Health Sciences, University of California, Davis, California. 9. Department of Pathology and Laboratory Medicine, University of California, Davis, California. 10. Research and Translational Development, Karyopharm Therapeutics Inc., Newton, Massachusetts. 11. Simon Cancer Center, School of Medicine, Indiana University, Indianapolis, Indiana. 12. Medical Service, Veterans Affairs Northern California Health Care System, Sacramento, California.
Abstract
BACKGROUND: Kidney cancer (or renal cell carcinoma, RCC) is the sixth most common malignancy in the United States and is increasing in incidence. Despite new therapies, including targeted therapies and immunotherapies, most RCCs are resistant to treatment. Thus, several laboratories have been evaluating new approaches to therapy, both with single agents as well as combinations. Although we have previously shown efficacy of the dual PAK4/nicotinamide phosphoribosyltransferase (NAMPT) inhibitor KPT-9274, and the immune checkpoint inhibitors (CPI) have shown utility in the clinic, there has been no evaluation of this combination either clinically or in an immunocompetent animal model of kidney cancer. METHODS: In this study, we use the renal cell adenocarcinoma (RENCA) model of spontaneous murine kidney cancer. Male BALB/cJ mice were injected subcutaneously with RENCA cells and, after tumors were palpable, they were treated with KPT-9274 and/or anti-programmed cell death 1 (PDCD1; PD1) antibody for 21 days. Tumors were measured and then removed at animal euthanasia for subsequent studies. RESULTS: We demonstrate a significant decrease in allograft growth with the combination treatment of KPT-9274 and anti-PD1 antibody without significant weight loss by the animals. This is associated with decreased (MOUSE) Naprt expression, indicating dependence of these tumors on NAMPT in parallel to what we have observed in human RCC. Histology of the tumors showed substantial necrosis regardless of treatment condition, and flow cytometry of antibody-stained tumor cells revealed that the enhanced therapeutic effect of KPT-9274 and anti-PD1 antibody was not driven by infiltration of T cells into tumors. CONCLUSIONS: This study highlights the potential of the RENCA model for evaluating immunologic responses to KPT-9274 and checkpoint inhibitor (CPI) and suggests that therapy with this combination could improve efficacy in RCC beyond what is achievable with CPI alone.
BACKGROUND: Kidney cancer (or renal cell carcinoma, RCC) is the sixth most common malignancy in the United States and is increasing in incidence. Despite new therapies, including targeted therapies and immunotherapies, most RCCs are resistant to treatment. Thus, several laboratories have been evaluating new approaches to therapy, both with single agents as well as combinations. Although we have previously shown efficacy of the dual PAK4/nicotinamide phosphoribosyltransferase (NAMPT) inhibitor KPT-9274, and the immune checkpoint inhibitors (CPI) have shown utility in the clinic, there has been no evaluation of this combination either clinically or in an immunocompetent animal model of kidney cancer. METHODS: In this study, we use the renal cell adenocarcinoma (RENCA) model of spontaneous murine kidney cancer. Male BALB/cJ mice were injected subcutaneously with RENCA cells and, after tumors were palpable, they were treated with KPT-9274 and/or anti-programmed cell death 1 (PDCD1; PD1) antibody for 21 days. Tumors were measured and then removed at animal euthanasia for subsequent studies. RESULTS: We demonstrate a significant decrease in allograft growth with the combination treatment of KPT-9274 and anti-PD1 antibody without significant weight loss by the animals. This is associated with decreased (MOUSE) Naprt expression, indicating dependence of these tumors on NAMPT in parallel to what we have observed in human RCC. Histology of the tumors showed substantial necrosis regardless of treatment condition, and flow cytometry of antibody-stained tumor cells revealed that the enhanced therapeutic effect of KPT-9274 and anti-PD1 antibody was not driven by infiltration of T cells into tumors. CONCLUSIONS: This study highlights the potential of the RENCA model for evaluating immunologic responses to KPT-9274 and checkpoint inhibitor (CPI) and suggests that therapy with this combination could improve efficacy in RCC beyond what is achievable with CPI alone.
Authors: B Escudier; C Porta; M Schmidinger; N Rioux-Leclercq; A Bex; V Khoo; V Grünwald; S Gillessen; A Horwich Journal: Ann Oncol Date: 2019-05-01 Impact factor: 32.976
Authors: Josephine F Trott; Jeffrey Kim; Omran Abu Aboud; Hiromi Wettersten; Benjamin Stewart; Grace Berryhill; Francisco Uzal; Russell C Hovey; Ching-Hsien Chen; Katie Anderson; Ashley Graef; Aaron L Sarver; Jaime F Modiano; Robert H Weiss Journal: Oncotarget Date: 2016-10-11