Targeting MIC to Augment Adoptive NK Therapy Using the Canine Soft Tissue Sarcoma Model

Project Summary Adoptively transferred natural killer (ATNK) cells have an established and likely growing role for the treatment of hematologic malignancies, particularly in the context of hematopoietic stem cell transplants. However, despite a growing understanding of the critical role these cells play in the immune response against solid tumors, multiple trials have failed to translate these findings to the clinic. One major reason for this disconnect may relate to the immune suppressive tumor microenvironment (TME). In our published studies, we have demonstrated that antibody B10G5 targeting the MHC I chain related molecule (MIC) that is broadly expressed by human solid tumors can significantly modulate TME, re-invigorating CD8 T cell activity, reviving, activating, and sustaining circulating NK cells. Our anti-MIC antibody serves as a partial agonist antibody that captures the immune suppressive sMIC secreted by tumors, to form an agonist for the NKG2D receptor to upregulate the key signaling molecule CD3z to enable NK cells better function through ADCC and NCRs. We also reported that B10G5 can increase the high affinity enable IL-2Ra expression on NK cells, and sensitize them to low doses of IL-2 in the TME. However, development and optimization of combination therapy with this antibody is challenging with current pre-clinical models as there are numerous differences between murine and human NK cells. Most importantly for our purposes is that the MIC gene is not present in mice. Although our group developed a MIC expressing murine models to overcome this, its power is limited in addressing questions related to NK cell combination therapies. To better model adoptive NK therapy, we have been studying canine soft tissue sarcomas (STS) in client-owned (pet) dogs as predictive models for human undifferentiated pleomorphic sarcoma (UPS) which is the human STS subtype most analogous to canine STS. We developed reliable protocols for generating canine NK cell products at therapeutic doses, from various sources, using procedures appropriate for the veterinary clinic and mirroring those used for humans. The Specific Aims are: Aim 1: To determine the safe and effective dose of B10G5 in activating endogenous NK cells infiltrating canine STS and reshaping the TME. We hypothesize that B10G5 will activate infiltrating NK cells, and possible CD8T cells, reshaping the STS tumor immune microenvironment for tumor control. Aim 2: To optimize the adoptive transfer of NK cells for STS. We hypothesize LD chemotherapy will promote persistence and proliferation of both allogeneic and autologous NK product. Aim 3: To determine if B10G5 will act synergistically with ATNK. We hypothesize that B10G5 will enable adoptively transferred NK cells to effectively eliminate canine STS.