Enhanced NK cell Immunotherapy for Treatment of Chemotherapy Refractory Sarcoma

Radiation therapy is a crucial treatment modality required to control soft tissue and advanced bone sarcomas. Despite technological advancements used to treat radioresistant sarcomas, local recurrence and metastasis continue to pose clinical challenges. Ionizing radiation can elicit anti-tumor responses by releasing tumor-specific antigens that are then visible to the immune system to promote potent T-lymphocyte priming, characterized as in situ vaccination. Radiation alone is rarely able to induce durable systemic antitumor immune responses. New immunotherapy drugs using antibody fragments such as bispecific antibodies and checkpoint inhibitors actively enhance the immune system to help fight cancer are approved for use in advanced disease settings or in conjunction with chemotherapy, but not for use with radiation therapy because their combination approach requires optimization. Recent work has shown that radiation upregulates immune targets in sarcomas. The recognition that radiation can expose sarcoma antigen to the immune system and upregulate immunotherapy targets warrants exploitation. Advanced radiation techniques such as stereotactic body radiation therapy (SBRT) permits large radiation doses to be precisely administered per treatment and is an attractive approach to combine with immunotherapy for several key reasons: Radiation dose can be escalated and delivered in only a few fractions (5 treatments) compared to standard, conventional radiation (25-35 treatments); SBRT is more immunostimulatory than a single ablative treatment or conventional radiation; SBRT shortens the time from diagnosis to multimodality therapy, limiting the potential for tumor progression. However, the impact of SBRT on the sarcoma immune landscape is crucial, particularly as we seek to combine it with novel immunotherapy approaches. Canine soft tissue and bone sarcomas have a similar pathologic appearance, clinical presentation, and biologic behavior to humans, leading to similar diagnostic and therapeutic approaches. The integration of comparative oncology methods that use pet dogs with spontaneously occurring tumors as models for human disease uniquely answers vital questions regarding the combination of immunotherapy and radiation therapy. A central, distinctive feature of this proposal is that we have produced an anti-sarcoma immunotherapeutic drug for dogs and humans for use with radiation that maximizes sarcoma killing by augmenting natural killer cell activity. Our overall hypothesis is that the innate immune system, usually in a state of inhibition in cancer patients, can be manipulated to combat sarcoma as a new alternative therapy in combination with state-of-the-art radiation therapy. We will combine two powerful disciplines in our radiation oncology “companion” dog program with our drug development program to advance our development of new sarcoma therapies.