Abstract A150: Effects of radioimmunotherapy on human and canine osteosarcoma microenvironment
Authors: Giri Sabeena , Allen Kevin J.H. , Uppalapati Maruti , Dadachova Ekaterina 
Published: December 2023

Introduction: Osteosarcoma (OS) is a type of primary bone cancer that predominantly affects children and adolescents with an unacceptably high mortality rate of 30% within 5 years of diagnosis.  Though several treatment options including radiotherapy, chemotherapy, and amputation surgery exist, these are either ineffective or very invasive. Also, no significant advancements in treatment options have occurred in the last 30 years. The incidence of OS among companion dogs is much higher than in humans and phenotypically OS is very similar between humans and canines. We are using a comparative oncology approach to OS treatment by developing radioimmunotherapy (RIT) which targets the insulin-like growth factor receptor type 2 (IGF2R) on OS cells. IGF2R is abundant in human and canine OS and has shown promise a novel target for RIT of OS using a comparative oncology approach. It is therefore important to investigate the mechanistic underpinnings of RIT efficacy by investigating its interaction with OS microenvironment to develop improved RIT regimens for OS.

Materials and Methods: Severe combined immunodeficiency (SCID) female mice bearing human and canine patient-derived OS xenografts were treated with  RIT  utilizing IF3, a novel full-length human mAb targeting IGF2R obtained by phage-display technology.  The IF3 antibody was radiolabeled with an alpha emitter 225Actinium (225Ac) or a beta emitter 177Lutetim (177Lu) radionuclides. The tumors were removed at 1, 3 and 7 days post-RIT and the effects of RIT on IGF2R-positive tumor cells, OS stem cells, and immune components of the tumor microenvironment such as natural killer (NK) cells and tumor-associated macrophages (TAMs) were assessed using quantitative immunohistochemistry (IHC).

Results: In the untreated tumors IHC detected the presence of IGF2R-positive tumor cells, OS stem cells, and immune components of the tumor microenvironment such as NK cells and TAMs,  in both human and canine OS tumors obtained from mouse models. Quantitative analysis of IHC results in the tumors post-RIT demonstrated a time-dependent  decrease in IGF2R-positive OS tumor cells and OS stem cells and an increase in TAMs and NK cells.

Conclusions: Deciphering the mechanisms of RIT interaction with tumor microenvironment can assist in the design of the clinical trials in companion dogs with OS, which will be followed by the trials in children with this cancer. Also, it supports combining RIT with immunotherapy targeting OS stem cells and other immune components of tumor microenvironments such as NK cells and TAMS, which can result in improved patient outcomes.

Citation Format: Sabeena Giri, Kevin J.H. Allen, Maruti Uppalapati, Ekaterina Dadachova. Effects of radioimmunotherapy on human and canine osteosarcoma microenvironment [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A150.