Children's Hospital Colorado Foundation Archives - Page 2 of 3

2018

Scholar Grant

Michael Verneris

Denver, CO

Targeting Pediatric Sarcoma with IL-15 Producing, CAR Expressing NK cells

“For children with rhabdomyosarcoma and osteosarcoma, there have been essentially no new therapeutic advances in three decades. In contrast, other childhood cancers such as leukemia have seen breakthroughs that use a patient’s own immune system to attack cancer cells. This approach, called chimeric antigen receptor T-cell therapy (CAR-T), was recently approved by the FDA. This therapy involves genetically modifying a patient’s own blood cells (called T cells) to specifically kill leukemia. Current CAR-T therapy has limitations and does not worked for sarcoma. Our goal is to utilize another blood cell, natural killer (NK) cells to create an “off the shelf” therapy. To do this we will target NK cells to sarcoma by using an CAR that recognizes a protein that is over-expressed by the sarcoma, called EGFR. As well, we will use induced pluripotent stem cells (iPSCs), generated from adult tissues, that can be turned into NK cells as starting material. We will use iPSCs because these cells are easily genetically manipulated and can produce unlimited NK cells. To improve the lifespan of the NK cells once they are given to patients, we will manipulate the iPSCs to produce a growth factor needed for NK cell survival. We will also develop techniques to make the NK cells migrate into the tumor, thereby enhancing tumor recognition and killing. We hypothesize that the above methods will improve how the immune system recognizes and kill cancer cells, leading to an effective new pediatric sarcoma therapy. The goals of the project are:

• Specific Aim 1: To clone and infect iPSCs that express NK-specific growth factors to help the cells persist in the circulation and kill tumor cells
• Specific Aim 2: To target NK cells to sarcoma using EGFR CARs
• Specific Aim 3: Devise methods to increase the homing of NK cells to sarcoma”

2018

Young Investigator

Masanori Hayashi

Aurora, CO

Targeting tumor heterogeneity as an anti-metastasis target in Ewing sarcoma

Although many children who are diagnosed with localized Ewing sarcoma become long-term survivors when treated with conventional chemotherapy, 30% will still relapse in a distant metastatic site. In many patients, the metastasis could occur in a distant, originally uninvolved site, despite complete control of the initially diagnosed localized tumor, suggesting that metastatic disease and the primary tumor are entirely distinct entities. Despite this observation, many targeted therapies that are currently being studied are focused on and measured by local tumor response and are based on the assumption that tumors are simply a collection of homogeneous cells. In this proposal, we seek to address this unmet need to study anti-metastasis therapy by focusing on how some cells within the local tumors become “super-charged” cells—known as Circulating Tumor cells (CTC)—that can comfortably travel through the blood stream to get to the distant organ. There are three major aims of this proposal:

Aim 1: Investigate how the Ewing sarcoma cells rely on Wnt signaling to create a diverse group of cells within the tumor to start the metastatic cascade.
Aim 2: Interrogate the CTC in mice models to find out what these cells rely on to survive.
Aim 3: Investigate how Ewing sarcoma cells change their behavior from tumor to CTC in patient samples.

At the conclusion of this proposal, we will learn how Ewing sarcoma generates and maintains CTC to accomplish metastasis through the use of Wnt signaling. Intervening in this process and capitalizing on our unique ability to identify and interrogate CTC, we will investigate how the application of novel Wnt inhibitors specifically target these rare cells that cause metastasis.