Abstract 5059: Breast cancer patient-derived xenograft models for pre- and co-clinical investigation of immune based therapies

Abstract

Abstract Breast cancer is a highly heterogeneous disease, with a heterogeneous prognosis. Patient-derived xenograft models (PDX) can reflect this heterogeneity and can be used to support the development of novel therapeutic strategies against breast cancer. Preclinical experiments with larger cohorts of breast cancer PDX can be used to model a clinical phase II study with new drugs or drug combinations. The predictive value of these preclinical trials is currently evaluated in co-clinical trials, where treatment effects are compared between patients and their corresponding PDX. We present results from our translational pre- and co-clinical studies in breast cancer immune therapy. As part of the EFRE-POP Project, we established PDX by collecting breast cancer tissue samples from surgery and engrafting them on immunodeficient mice. The tissues were obtained from patients with disease progression after chemotherapy with three to four drugs. PDXs have been successfully engrafted, phenotypically characterized and drug-screened. The PDXs were tested for response to the standard of care therapies. The staining for estrogen/progesterone/androgen/Her2 receptors, Ki-67, and CK5/6 of the original tumor and the PDX were comparable. The patient tumors and the breast cancer PDX models were further analyzed for the expression of PD-L1. We identified four patients that had received PD-1 or PD-L1 antibodies after a sample (used to establish a corresponding PDX) was obtained. To evaluate the response of our preclinical PDX models to immune checkpoint inhibitors, we engrafted mice with a human immune system either by transplanting allogeneic hematopoietic stem cells (HSC) or allogenic PBMC's from healthy donors. Besides, we were able to obtain PBMC's from the patients to set up an autologous model. The patient-derived tumors were transplanted to these humanized mice and after successful engraftment treated with the PD-1 or PD-L1 antibodies corresponding with the clinical treatment of the patient. In summary, humanized PDX of refractory tumors have been established and the first pre-clinical evaluation of response to immune therapy provides evidence that xenografts respond in a qualitatively similar manner as the patient. This suggests a translational relevance of the described pre-clinical models. Citation Format: Annika Wulf-Goldenberg, Verena Kiver, Maria Stecklum, Bernadette Brzezicha, Philipp Jurmeister, Caroline Schweiger, Jens-Uwe Blohmer, Ulrich Keilholz, Jens Hoffmann. Breast cancer patient-derived xenograft models for pre- and co-clinical investigation of immune based therapies [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 5059.