Flagging the Merited Lesions-Fibroblast 1 and 4 Imaging to Map the Key Avid Domains for Spiked Antigenicity Using SBRT In Situ Vaccination and Metronomic Radiation with Anti PDL-1 Therapy for Augmented Abscopal-Radscopal Responses in Disseminated Cancers

Abstract

<h3>Purpose/Objective(s)</h3> Immune stimulating effects of SBRT (stereotactic body radiotherapy) for releasing tumor antigens and the immuno-modulatory property of low dose radiation has been under evaluation over years. Conceptual Radscopal effect for lesions receiving a non-tumoricidal scattered low dose radiation showing abscopal responses led to the concept of combining SBRT to highly avid larger metastatic lesions and low dose radiation to smaller lesions is exciting. However, choosing the right lesions for SBRT to release adequate and appropriate tumor antigen spike to cause a systemic response has been a challenge and area of interest. Cancer Associated Fibroblasts (CAF) 1 and 4 can produce growth factors and cytokines such as transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF) to promote angiogenesis and recruit immunosuppressive cells into the tumor stroma leading to immune evasion and resistant immune microenvironment. Fibroblast Activated protein tagged to CAF 1 and 4 whole body Molecular imaging aids us in identifying regions. Based on the avidity values of CAF 1 and 4 tagged imaging, the most immune resistant (CAF Rich) target lesions were chosen for SBRT in our study. Prominent usage of Anti PDL-1 inhibitors has been proven to be beneficial in disseminated cancers, concept of SBRT with metronomic radiation could be used as immune potentiator with accurate mapping of Immune resistant areas. <h3>Materials/Methods</h3> Five patients with disseminated cancers with indications for approved immune check point inhibitors were recruited after institutional ethical committee clearance. Patients received at least 3 cycles of check point inhibitor therapy prior to initiation of immuno-rad therapy. Based on CAF molecular imaging, 1-3 lesions with maximal avidity >10 standard uptake value were chosen for SBRT to a dose of 24 Gy in 3 fractions while all other metastatic less avid smaller lesions received Low dose 1 Gy metronomic radiotherapy using Image guided radiotherapy. Patients were continued on immunotherapy for 3 more cycles before a re-assessment molecular imaging was done. <h3>Results</h3> Nasopharyngeal (NPC), hepatocellular (HCC), 2 lung and renal cell cancer (RCC) patients were recruited. No grade 2 or above normal tissue toxicity was noted. <h3>Conclusion</h3> Effectively tackling the tumor immune evasion mechanisms by choosing the right lesions for SBRT acting as an in situ-vaccination by extensive release of antigens based on individual CAF biomarker profiling would ultimately aid in improving responses to Immunotherapy. The early results of our study are encouraging.