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Small animal imaging is increasingly recognized as an important component of translational cancer research. Perhaps the most significant contribution of preclinical imaging is that it provides information in a living system. Small animal imaging is essential in building a bridge from basic science to the clinic by providing the confidence necessary to move new cancer therapies to patients. However, there is a lot of variability and lack of standardization in preclinical imaging where a Tower of Babel of imaging acquisition, reconstruction, and analysis methods co-exist. There is a clear need of a common language by adopting standards for preclinical quantitative imaging methods that are pragmatic, rigorous and sufficiently robust to provide consistent and trustworthy data that will serve the scientific community and in particular co-clinical trials.

Our long-term goal is to move small animal imaging science forward to the point that the incorporation of these standardized imaging techniques is routine in the daily practice of cancer researchers. At the clinical level, QIBA aims to standardize approaches for quantitative imaging [1], but no such efforts exist at the preclinical level. Our project will spearhead such efforts for micro-MRI and micro-CT to support a multi-institutional, randomized phase II sarcoma clinical trial.

Soft tissue sarcomas represent a diverse group of mesenchymal malignancies. An estimated 11,930 new soft tissue sarcomas cases occurred across all ages and caused 4,870 deaths in the United States in 2015 [7]. Given the relative rarity and complexity of soft tissue sarcomas, they remain understudied and pose a significant therapeutic challenge. The primary treatment modality for most soft tissue sarcomas is surgical resection. For patients with large or high-grade tumors, radiation therapy is frequently used in the neoadjuvant or adjuvant setting to improve local control [8, 9]. Following local therapies, approximately 50% of patients with large, high-grade soft tissue sarcomas develop lung metastases. For most subtypes of soft tissue sarcomas, the value of adjuvant chemotherapy remains controversial [10]. After metastases occur, available systemic therapies can temporarily decrease disease burden, but median survival is 12 to 18 months [11-15]. Thus, alternative therapeutic approaches are urgently needed to reduce the number of soft tissue sarcoma patients that develop metastases and thereby improve overall survival.

To treat micrometastatic deposits of sarcoma in patients with clinically localized disease, this project proposes that the host immune response can be stimulated by the combination of radiotherapy and immune checkpoint inhibitors, such as the anti-PD-1 antibody pembrolizumab.

The scientific premise of the proposed co-clinical trial is based on preclinical data from others demonstrating synergy between anti-PD-1 treatment and radiotherapy [4, 16-25], our own preliminary data, and clinical trial results (SARC028) establishing responses of metastatic sarcoma to pembrolizumab. During tumor development, cancers can evolve to suppress anti-tumor immune activity, for example, by downregulating antigen-presenting proteins [26-28]. Moreover, tumors can secrete cytokines that inhibit effector T-cell responses and stimulate immunosuppressive regulatory T-cells (Tregs) and myeloid-derived suppressor cells (MDSCs) [28, 29]. Data from phase I and II clinical trials in metastatic melanoma and several preclinical studies in various tumor models indicate that radiotherapy enhances the therapeutic effect of immune checkpoint inhibitors such as antibodies targeting PD-1 [4, 16, 17, 19, 30, 31]. Radiation therapy may augment the anti-tumor immune response by inducing exposure of new tumor antigens through cross presentation, upregulating major histocompatibility complex-I (MHC-I) expression, stimulating chemokines that recruit cytotoxic T-cells, and upregulating death receptors which promote cytotoxic T-cell activity [3]. When immune checkpoint inhibitors are administered in the absence of radiation therapy, tumor mutational load correlates with the efficacy of immunotherapy [32-35].

The hypothesis of our co-clinical trial is that immune stimulation by radiotherapy combined with immune checkpoint blockade will reduce or eradicate micrometastatic disease and improve metastasis-free survival in mice and patients with soft tissue sarcoma.

The clinical trial focused on sarcoma will use MRI to image the sarcoma before and after radiation therapy to assess efficacy and to plan surgery procedures. Similarly, we will use micro-MRI in our preclinical work. Specialized MRI hardware for mouse imaging includes high-field, small-bore magnets, gradient systems with rapid rise times and high amplitudes, and high sensitivity radiofrequency coils. The main advantage of increasing the field strength is a higher signal to noise ratio (SNR), which can then be traded for improved spatial resolution or shorter scan times. Our group has more than 30 years’ experience in small animal MRI [36]. Reference [37] is a recent example of the type of novel approach we have developed for preclinical cancer imaging.

The clinical trial uses chest CT in follow up procedures to investigate the presence of lung metastases. Consequently, we will use micro-CT of the lung in our preclinical studies. We have also pioneered the development of micro-CT systems with novel cardio-respiratory gating strategies [38] to image lung nodules[39-41]. We possess the necessary know-how to optimize/standardize micro-MRI and CT.