Metastatic osteosarcoma has a poor prognosis, yet systemic standard of care therapies renders patients with great morbidity and life-long disabilities. Thus, there is an urgency to discover less toxic and more effective therapies for this patient population. The body’s natural defense against cancer relies on the immune system’s potential to recognize and destroy cancer cells. Immunotherapy provides an alternative or adjunct to current standard treatments for decreasing cancer-related mortality while also having the potential to decrease morbidity. Early studies on targeted immunotherapy and chimeric antigen receptor modified T cellular therapy have proven effective in relapsed hematologic cancers. These modalities are still elusive in many solid tumor malignancies. Immune checkpoint inhibition has also been discovered to be a significant factor in the immune system’s ability to destroy cancer cells. Overcoming this barrier may serve as a necessary component to maximizing the immune system’s function against malignant cells. With the profound similarities of naturally-occurring canine and human osteosarcoma, dogs serve as the most ideal large animal model to study targets against this disease. Our preliminary data suggests that targeted CAR-T cells are effective in destroying osteosarcoma cells, and the addition of checkpoint inhibitor blockade may improve this killing potential. Our third generation CAR is both innovative and effective, simultaneously targeting two highly expressed cancer cell surface antigens on osteosarcoma cells. A dual antigen target is strategic in overcoming tumors’ natural defense to immune destruction via antigen escape, while also avoiding low antigen expression limitations. Furthermore, the dual target CAR can be applied to other sarcomas and malignancies with one or both of the target antigens, thus creating a versatile therapy. With strong in-vitro data, we will conduct a clinical trial on mice and dogs with osteosarcoma utilizing this CAR-T cell design in addition to checkpoint inhibitor blockade. We will be able to manipulate immune regulation through knockout mice and in-vivo blockade to determine the most influential combinatorial therapy. Murine data will then be applied to a clinically relevant canine osteosarcoma model. We will further assess the degree of these two target antigens across all sarcomas and measure the cytotoxic potential of the dual-antigen CAR against them. Our hypothesis is that large numbers of anti-GD2-GD3 CAR modified T cells can be generated from peripheral blood samples of dogs, and induce efficacious tumor cell death through combinatorial targeting of regulatory pathways.
Matthew Cascio, DO, University of Florida
Recipient of the: Dr. Richard and Valerie Aronsohn Memorial Research Award