AACR 2014: Humanized Mouse Models for Personalized Preclinical Testing of Monoclonal Antibodies Targeting Immune Checkpoints
Humanized mouse models for personalized preclinical testing of monoclonal antibodies targeting immune checkpoints
Gilson S. Baia1, David Vasquez1, Daniel Ciznadija1, Brandy Wilkinson1, David Sidransky2, Amanda Katz1, Keren Paz1. 1Champions Oncology, Inc, Baltimore, MD; 2The Johns Hopkins School of Medicine, Baltimore, MD
The blockade of immune checkpoints with monoclonal antibodies (mAbs) is a promising therapeutic avenue, with durable objective responses observed in patients with solid tumors, particularly melanoma, non-small cell lung cancer (NSCLC) and renal cell carcinoma. Preclinical models that recapitulate a functional human immune system will therefore be essential tools for the continued investigation of immunotherapy approaches. Champions Oncology is engaged in advanced personalized solutions and our TumorGraft models have been developed and extensively characterized as a platform for use in personalizing cancer patient care, as well as pharmaceutical development. However, because TumorGrafts are established by engrafting patient tumors into immune-deficient mice, the therapeutic efficacy of immune-modulatory drugs cannot be directly examined. To circumvent this limitation, we reconstituted the human immune system by engrafting human hematopoietic cells (HLA-A2; CD34+) into immune-compromised mice (PrkdcscidIl2rgtm1Sug) carrying the scid mutation and a targeted mutation of the Il2r-gamma gene. Ten to twelve weeks later, mature CD45+ human T cells could be detected in these mice, at which time TumorGrafts were established, followed by drug-sensitivity testing with various mAbs targeting the immune system. Fifty six well-established melanoma, colorectal, breast and lung TumorGraft models were characterized and selected with regard to their HLA type and other molecular characteristics such as BRAF mutation status (in melanoma) and KRAS mutation status (in colorectal and lung cancer) as well as expression of PD-L1. With the present study, we demonstrated the potential of combining the humanized mouse with Champions TumorGraft to generate a preclinical platform for assessing the therapeutic value of mAbs targeting immune checkpoints in various solid tumors.