University Hospitals Cleveland Medical Center (DBA University Hospitals Case Medical Center) Archives

2019

Young Investigator

Kristen Vanheyst

Cleveland, OH

Executive Summary: Osteosarcoma (OS) is the most prevalent aggressive primary malignancy of the bone affecting children and young adults. Approximately 10% to 20% of patients have metastatic disease at initial presentation. The most common site for disease metastasis and recurrence is the lungs. Although overall survival in patients with OS has improved with advances in therapy, there have been no significant improvements in survival outcome in patients with metastatic disease. For this reason, novel therapeutic approaches are desperately needed. Recent studies suggest that tumor-associated Vascular Cell Adhesion Molecule 1 (tVCAM-1 or CD106) plays a critical role in the metastatic progression of various tumors. Indirect evidence from these studies suggest that VCAM-1/ a4ß1 integrin signaling promotes tumor survival and metastatic progression by changing the tumor niche and associated immune response. Our ongoing preclinical data using spontaneous, high-grade murine OS cell lines from Balb/c mouse (H-2d), K7 and K7M2 (derived from in vivo K7 metastasis) support the hypothesis that interfering VCAM-1/a4ß1 signaling between pulmonary metastatic osteosarcoma (pOS) and lung macrophages (MACs) by down-regulating VCAM-1, depleting MACs or blocking VCAM-1/ a4ß1 signaling reduces pulmonary metastatic OS (pOS). Additionally, using agents that modify tumor-associated macrophages from M2 to M1 may be beneficial in treating pOS. Our data supports our ongoing development of a clinical trial (NCT038011886) that I have composed as well as future trials using immunotherapy as a therapeutic option for pOS patients. Additional results from this current proposal will provide valuable data for additional clinical trials to combat this devastating disease in the very near future.

2018

Young Investigator

Yamilet Huerta

Cleveland, OH

Exploring in vitro and in vivo interaction dynamics between CD123-CD3 Engager CAR T cell and AML

Leukemia is the most common type of childhood cancer. Acute lymphoblastic leukemia (ALL) represents the vast majority (~75%) of childhood leukemia. However, acute myelogenous leukemia (AML) accounts for 20% of childhood leukemia and continues to represent a big challenge to the pediatric oncology field. AML is typically treated with intensive combination chemotherapy. Unfortunately, despite such aggressive therapies including chemotherapy and stem cell transplant, the prognosis of a child with recurrent or refractory AML remains poor. For this reason newer therapies are needed. Recently, innovative therapies utilizing our own immune system are being studied as a resource to fight cancer. T cells are immune cells in our body that become activated and can specifically kill harmful invaders. Engager (ENG) T cells are genetically engineered T cells that are capable of binding to specific AML cells and, at the same time, “engaging” neighboring (bystander) non-engineered T cells to mount an enhanced immune response to kill cancerous cells such as AML.

The aim of this research project is to gain knowledge of the mechanism by which leukemic myeloid cells can be killed using this novel immunotherapy technique, and to translate our findings toward cellular therapies that can be adapted for use in clinical trials. This will be accomplished by:

• First, using mice models to analyze cellular mechanisms by which ENG T cells kill AML cells that express a specific protein called CD123.
• Second, using mice models to investigate if the activation of bystander non-engineered T cells by ENG T cells is indeed critical to the antitumor immune response.

By understanding the way ENG T cells work, it will support the use of a cutting-edge, targeted immunotherapy that may help to improve poor clinical outcomes and provide more options to help children with AML.