Abstract 5632: Targeted immunotherapy with SV-BR-1-GM: Mechanism of action and companion diagnostic development

SV-BR-1-GM is a GM-CSF-engineered whole-cell targeted immunotherapy derived from a breast cancer cell line (SV-BR-1). We are currently assessing SV-BR-1-GM in a phase I/IIa clinical trial in metastatic and locally recurrent breast cancer (ClinicalTrials.gov identifier NCT03066947). Subjects who fail to respond with tumor regression are offered participation in a “roll-over” study in which an immune checkpoint inhibitor (pembrolizumab or ipilimumab) is added to the SV-BR-1-GM regimen (ClinicalTrials.gov identifier NCT03328026). To identify patients likely to respond to SV-BR-1-GM we are co-developing a companion diagnostic. In a pilot phase I study with four evaluable patients, one subject (A002), with metastatic breast cancer, experienced systemic tumor regression including in soft tissue, lung, and brain lesions. In contrast to the three nonresponders, A002 matched with SV-BR-1-GM at both a class I (HLA-A) and a class II (HLA-DRB3) HLA allele. Strikingly, SV-BR-1-GM cells also express HLA class II “accessory” factors such as HLA-DMA and -DMB, HLA-DRA, and CD74 (encoding invariant chain and CLIP), and immunostimulators such as IL6, Il18, and KITLG, and the damage-associated molecular pattern (DAMP) protein HMGB1. SV-BR-1-GM cells do not express the T cell co-stimulatory ligands CD80 or CD86. These findings are consistent with a potential to activate previously primed but not naive CD4+ T cells. In agreement, peptide-pulsed SV-BR-1-GM cells selectively activated peptide-HLA specific, pre-primed T cells. Given this functional data and the expression of the “immune signature”, comprised of factors including those mentioned above, we hypothesized that SV-BR-1-GM cells can act as antigen-presenting cells (APCs) and present tumor-associated antigens (TAAs) directly to HLA-matched T cells, which in turn would induce an immune response directed to the patients9 tumors. To evaluate this hypothesis, we have begun developing bioassays for assessing antibody and T cell responses to SV-BR-1-GM. Here, we present data on SV-BR-1-GM9s molecular makeup and development of anti-SV-BR-1-GM humoral and cellular immune responses. Our findings support SV-BR-1-GM acting as antigen-presenting cells for HLA class I and class II restricted immune responses. Citation Format: Markus D. Lacher, Sanne Graeve, Charles L. Wiseman, Ying Y. Kong, William W. Kwok, William V. Williams. Targeted immunotherapy with SV-BR-1-GM: Mechanism of action and companion diagnostic development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5632.