STING-Activating CAR-NK Cell Therapy for the Systemic Treatment of Rare Gynecological Cancers
Abstract
Uterine sarcomas are rare and lethal cancers with inadequate screening and treatment options and dismal clinical outcomes. These cancers also disproportionately impact Service Members, relative to the general population, adversely impacting mission readiness and highlighting the urgent need for curative therapies. Uterine sarcomas typically escape immune surveillance and are largely unresponsive to current immunotherapies that have revolutionized the standard of care for other tumor types. A central cause for the lack of efficacy of current immunotherapies is the immunosuppressive tumor microenvironment in these tumors, where there is limited infiltration and activation of effector CTLs and natural killer (NK) cells within the tumor core. Our long-term goal is to convert this immunologically cold microenvironment into an immunoreactive one that drives immune tumor rejection. This project addresses the Fiscal Year 2021 Rare Cancers Research Program Focus Area of Therapy, with the central goal of developing and testing powerful new anticancer therapeutic strategies. Our overall objective for this proposal is to develop novel, NK cell-based immunotherapies that dynamically reprogram the tumor immune landscape and induce potent anti-tumor immune responses, resulting in long-term or even permanent disease remissions. Based on our preliminary data, we hypothesize that immune evasion in uterine sarcomas can be overcome with immunotherapies in which NK cells are armed with engineered chimeric antigen receptors (CAR) designed to generate potent and diffusible immune alarm molecules, known as cyclic dinucleotides (CDNs), specifically within tumors and metastases. These CDNs will in turn activate the innate immune receptor STING (stimulator of interferon genes), mobilizing tumor-targeting cytotoxic T-cells and infiltrating NK cells to trigger immune tumor rejection. With respect to outcomes, these studies promise to generate key evidence supporting STING- activating CAR-NK cells as a breakthrough therapeutic paradigm for the treatment of rare uterine sarcomas cancer, with applications both as a monotherapy and as a combination treatment with NK checkpoint blocking antibodies now in clinical trials. The engineered CAR- NK cell lines generated by this research program will allow for rapid translation into clinical testing – expected within 2-3 years after the project is completed – of therapeutic combinations that are more likely to be effective. Thus, the successful completion of this research program will accelerate translational, bench-to- bedside studies, resulting in direct patient benefit and improved health and well-being of female Service Members, Veterans, and their family members.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210897
Entities
People
- Douglas E. Feldman
Organizations
- United States Army
- University of Southern California