Abstract LB-391: Combination of insulin-like growth factor-1 receptor/insulin receptor (IGF1R/IR) antagonist with anti-PD-L1 antibody blocks triple-negative breast cancer (TNBC) progression
Authors: Hamilton Nalo M. , Marquez-Garban Diana C. , Burton Lorena P. , Comin-Anduix Begonya , Garcia Alejandro J. , Vadgama Jaydutt V. 
Published: September 2020

Abstract
Triple-negative breast cancer (TNBC) affects only about 10-15% of women with breast cancer (BC) but accounts for almost 50% of all BC deaths. At this time, development of targeted treatments for TNBC is urgently needed. Insulin-like growth factor-2 (IGF2) is highly expressed in TNBCs in African-American and Latina patients. Since hormone receptors, like insulin-like growth factor-1/insulin (IGF1R/IR, are known to be enriched and to cross-communicate in subtypes of TNBC, we assessed effects of IGF1R/IR antagonists on proliferation of human and murine TNBC cells in vitro. Combination treatment of BMS-754807 (IGF1R/IR) with NVP-AEW541 (IGF1R inhibitor) reduced proliferation of human MDA-MB-231, BT549, HCC1937 and murine 4T1 TNBC cells in vitro (P&lt;0.001). Moreover, combination treatment using BMS-754807 and NVP-AEW541 significantly reduced MDA-MB-231 tumor xenograft progression in vivo (P&lt;0.001). IHC study of tumor tissues from in vivo experiments confirmed reduced Ki-67 expression with combination treatments. Among breast cancer subtypes, TNBC is characterized by significant numbers of tumor infiltrating lymphocytes (TILs), a predictive marker for response to immunotherapy. Further, recent reports from clinical trials using immune checkpoint inhibitors demonstrate that a subset of TNBC patients respond to treatment with immune checkpoint inhibitors (ICIs). It is also notable that increased expression of IGF1Rs are identified on immune cells responsible for mounting adaptive and humoral immune responses. Using murine 4T1 TNBC implants in syngeneic, immune-competent BALB/c mice, we find that combination treatment with BMS-754807 and anti-PD-L1 antibody significantly blocks tumor progression as compared to both controls and with either agent used alone (P&lt;0.0001). In addition, single cell analysis of the tumor microenvironment after treatment with BMS-754807 alone or combined with nti-PD-L1 antibody combination therapy shows a significant reduction in myeloid-derived suppressor cells (MDSCs). Moreover, BMS-754807 combined with anti-PD-L1 antibody increased infiltrating effector T cells and significantly enhanced the T central memory population (Tcm) (P&lt;0.01). Functionally, it is reported that Tcm subsets of immune cells produce effector cytokines in response to antigens and can readily proliferate and differentiate into effector cells. Use of immunotherapy is a promising management option for a subset of TNBC patients, and combination treatments using IGF1R antagonists with immune checkpoint inhibitor may constitute a new treatment strategy to combat this deadly disease. [Funding by NCI U54 CA1433930; California Breast Cancer Research Program; UCLA Jonsson
Citation Format: Nalo M. Hamilton, Diana C. Marquez-Garban, Lorena P. Burton, Begonya Comin-Anduix, Alejandro J. Garcia, Jaydutt V. Vadgama. Combination of insulin-like growth factor-1 receptor/insulin receptor (IGF1R/IR) antagonist with anti-PD-L1 antibody blocks triple-negative breast cancer (TNBC) progression [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-391.