Osteosarcoma(OS) is the most common malignant primary bone tumor with metastasis being the predominant cause of death. Unfortunately, OS is refractory to immunotherapies. Histotripsy(HT) is an immunomodulatory mechanical focused ultrasound ablation modality that promotes the release of tumor antigens. We hypothesize that HT will enhance anti-CTLA4 efficacy and lead to anti-tumor activity, aiding in mitigation of metastatic disease.
We employed a preclinical syngeneic subcutaneous OS model by implanting DLM8 cells in C3H/HeN mice to identify acute and chronic immunomodulation and survival benefit caused by HT+anti-CTLA4. Canine OS patients were enrolled into clinical trials to evaluate safety of HT+anti-CTLA4.
We observed local tumor control, intratumoral transcriptional reprogramming, along with B-cell activation and expansion of splenic memory T cells in combination treated mice at 14 days post-treatment. Combination therapy significantly suppressed contra-lateral tumors in bilateral tumor model studies. Combination treatment resulted in increased survival compared to untreated. Mice with complete tumor regression were rechallenged with tumors implanted in contra-lateral flank and rejected rechallenge. HT was well tolerated by canine patients and minimal immune related adverse events were observed in canine patients.
Overall, the combination of HT and anti-CTLA4 show efficacy in murine mouse models and promise in canine clinical trials.