Role of noninvasive molecular imaging in determining response

Abstract

The intersection of immunotherapy and radiation oncology is a rapidly evolving area of preclinical and clinical investigation. The strategy of combining radiation and immunotherapy to enhance local and systemic antitumor immune responses is intriguing yet largely unproven in the clinical setting because the mechanisms of synergy and the determinants of therapeutic response remain undefined. In recent years, several noninvasive molecular imaging approaches have emerged as a platform to interrogate the tumor immune microenvironment. These tools have the potential to serve as robust biomarkers for cancer immunotherapy and may hold several advantages over conventional anatomic imaging modalities and contemporary invasive tissue acquisition techniques. Given the key and expanding role of precision imaging in radiation oncology for patient selection, target delineation, image guided treatment delivery, and response assessment, noninvasive molecular-specific imaging may be uniquely suited to evaluate radiation/immunotherapy combinations. Herein, we describe several experimental imaging-based strategies that are currently being explored to characterize in vivo immune responses, and we review a growing body of preclinical data and nascent clinical experience with immuno-positron emission tomography molecular imaging as a putative biomarker for cancer immunotherapy. Finally, we discuss practical considerations for clinical translation to implement noninvasive molecular imaging of immune checkpoint molecules, immune cells, or associated elements of the antitumor immune response with a specific emphasis on its potential application at the interface of radiation oncology and immuno-oncology.

Figure 1

Imaging changes in response to immunotherapy. (A-C) Axial contrast-enhanced computed tomography (CT) scan demonstrating pseudoprogression in a patient treated with immunotherapy for advanced lung cancer. Marked interval enlargement of right paratracheal lymph node (arrow) and development of new prevascular mediastinal adenopathy (arrow head) 6 weeks after treatment compared with baseline (A-B). Follow-up CT scan 6 weeks later (12 weeks; C) demonstrates interval decrease in right paratracheal node and disappearance of other nodes. (D-G) CT and fused [¹⁸F]FDG positron emission tomography/CT scan of metastatic melanoma patient on-treatment with immunotherapy with development of new FDG-avid mediastinal/hilar adenopathy (arrows, D-E). Discontinuation of therapy because of suspected immune-related adverse event. Repeat imaging 6 weeks after treatment termination (F-G) demonstrated substantial decrease in size and avidity of nodes. Biopsy test results demonstrated sarcoid-like reaction and no evidence of malignancy. (H-I) Pre- and posttreatment nonenhanced axial CT images in patient with metastatic renal cell carcinoma treated with stereotactic body radiation therapy to posterior left lung lesion, followed by high-dose interleukin-2 with development of fibrotic changes (red) in site of stereotactic body radiation therapy and resolution of nonirradiated nodule (blue) in contralateral lung. Treatment-related radiographic changes complicate assessment of local control., Images adapted with permission for reuse ©2018 American Cancer Society and ©2012 American Association for the Advancement of Science.