Abstract 2784: Growth of patient derived tumor xenograft (PDX) in NOD/SCID mice reconstituted with human umbilical cord blood (UCB) CD34+ cells.
Authors: An Xiaoyu (Annie) , Yang Mengmeng , Wu Ran , Liu Jinping , Chen Taiping , Wery Jean-Pierre , Chen Yiyou , Li Henry 
Published: August 2014

Patient derived xenograft (PDX) is closely reflective of tumor in patient for both histopathological and genetic profiles 1, 2. It thus becomes widely accepted as model of choice to evaluate anticancer agents with improved predictive power. However, current PDX (HuPrime® 1.0/2.0) still has limitations, including growth in an environment lacking functional immunity, particularly that of human. Human immune functions have been successfully reconstituted in the same types of immunodeficient mice that were also used for engrafting PDX. This type of humanized mice with functional human immune system are established usually through engraftment of stem cells containing human CD34+ cells isolated from fetal liver, peripheral blood or umbilical cord blood (UCB). It is therefore also plausible to engraft both patient tumor and normal functional human immune system to a single recipient mouse so that tumors would grow in an environment even more similar to that of patients, and yield an even more predictive experimental model. This is particularly so for evaluating biologics or any immune modulating agents.

In the present study, we engrafted CD34+ UCB (hematopoietic stem cell enriched population) into NOD/SCID mice and demonstrated full reconstitution of human hemopoiesis, including myelopoiesis, lymphopoiesis (both T and B lineages), growth of dentritic cells (DCs), macrophage and monocytes, and growth of natural killer cells (NKs). These cells can be found in abundance in bone marrow, spleen as well as peripheral blood. We also further demonstrated the normal immune functions in the reconstituted mice (HuMICE™), including production of human cytokines such as GM-CSF and IL-3, etc.

Meanwhile, we also engrafted a previously established non-small cell lung cancer PDX (HuPrime®) model (LU25033 and LU0387) into the CD34+ UCB reconstituted NOD/SCID mice. Our preliminary results demonstrated that the tumor in the normal human immune system grow well, with maybe slight slower rate than the tumors in mice without reconstitution. We have observed significant infiltration of various human immune cells into the xenograft tumors. We are presently evaluating this type of new PDX models (HuPrime™ 3.0) by treating them with existing antibody therapeutics. Our preliminary data showed that the presence of human immunity, such as human NK-mediated ADCC, may have slight enhanced anti-tumor effect of antibody drug in HuPrime™ 3.0 than in HuPrime™ 2.0 (no human immune-reconstitute). We are currently assessing the role of the reconstituted immune function played in a biologic drug effect. We believe that HuPrime™ 3.0 could represent a more predictive model than those without functional immunity.

Citation Format: Xiaoyu (Annie) An, Mengmeng Yang, Ran Wu, Jinping Liu, Taiping Chen, Jean-Pierre Wery, Yiyou Chen, Henry Li. Growth of patient derived tumor xenograft (PDX) in NOD/SCID mice reconstituted with human umbilical cord blood (UCB) CD34+ cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2784. doi:10.1158/1538-7445.AM2013-2784