Abstract PD4-04: Leronlimab, a humanized monoclonal antibody to CCR5, restrains breast cancer metastasis and enhances cell death induced by DNA damaging chemotherapies

Abstract

Abstract Purpose of the study. To define the role of CCR5 in metastasis of breast cancer cells using a humanized monoclonal antibody to CCR5 (Leronlimab). CCR5, is a G protein coupled receptor that is normally expressed on immune cells. CCR5 expression is increase selectively in adult and pediatric malignancies including breast cancer (BCa), prostate cancer, pancreatic cancer, colon cancer, melanoma). In studies of >2,200 patients with breast CCR5 was overexpressed in >50% of human BCa, primarily in triple negative BCa (TNBC), correlating with poor outcome. Small molecule CCR5 inhibitors block breast and prostate cancer metastasis, but have known serious adverse events. Expression of CCR5 has been linked to both tumor immune heterogeneity and canonical check point inhibitor responses. CCR5 is activated by diverse ligands identified in the tumor microenvironment (CXCL13 (BCA-1), CCL3 (MIP1α), CCL3L1, CCL4 (MP-1β), CCL5 (RANTES), CCL8 (MCP2), CCL11 (Eotaxin), CCL13 (MCP-4), CCL16 (HCC-4). CCR5+ BCa epithelial cells have characteristics of cancer stem cells, initiating tumors and metastasizing in mice. CCR5 reintroduction into CCR5 negative BCa cells promotes tumor metastases and induces DNA repair gene expression and activity. The CCR5 inhibitor Leronlimab has been used in treatment of >750 patients with HIV, and met its primary endpoints in a phase III pivotal study for HIV, without significant adverse events reported. A CCR5 targeted cancer clinical trials (phase 1) using a small molecule inhibitor with the check point inhibitor Pembrolizumab opened to accrual in late 2018 NCT03274804. Results. Leronlimab augmented BCa cell killing by DNA damage inducing agents. Leronlimab bound to CCR5 expressed in human breast cancer cell lines, abrogated CCL5 induced Ca+2 flux, blocked 3-d matrigel invasion and blocked metastasis of MDA-MB-231 cells in murine xenografts. At 7 weeks, metastatic BCa tumor burden was reduced >98% by leronlimab. CCR5 was identified on patients' circulating tumor cells (CTC). Based on these studies a phase 1b/2 clinical trial was approved for Leronlimab and carboplatin treatment of metastatic TNBC (NCT03838367) and granted fast track designation in May 2019. The trial monitors CTC in response to leronlimab and progression free survival, Conclusions. Leronlimab binds CCR5 in BCa cells, blocking breast cancer cellular metastasis with a clinical trial currently accruing. As CCR5 augments DNA repair and is expressed selectively on cancerous but not normal breast epithelial cells, Leronlimab may enhance the tumor specific activities of DDR-based treatments, allowing a reduction in dose of standard chemotherapy. Citation Format: Richard G Pestell, Massimo Cristofanilli, Hallgeir Rui, Xuanmao Jiao, Min Wang. Leronlimab, a humanized monoclonal antibody to CCR5, restrains breast cancer metastasis and enhances cell death induced by DNA damaging chemotherapies [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD4-04.