Immuno-PET Monitoring of CD8+ T Cell Infiltration Post ICOS Agonist Antibody Treatment Alone and in Combination with PD-1 Blocking Antibody Using a 89Zr Anti-CD8+ Mouse Minibody in EMT6 Syngeneic Tumor Mouse.

PURPOSE: The presence and functional competence of intratumoral CD8+ T cells is often a barometer for successful immunotherapeutic responses in cancer. Despite this understanding and the extensive number of clinical-stage immunotherapies focused on potentiation (co-stimulation) or rescue (checkpoint blockade) of CD8+ T cell antitumor activity, dynamic biomarker strategies are often lacking. To help fill this gap, immuno-PET nuclear imaging has emerged as a powerful tool for in vivo molecular imaging of antibody targeting. Here, we took advantage of immuno-PET imaging using 89Zr-IAB42M1-14, anti-mouse CD8 minibody, to characterize CD8+ T-cell tumor infiltration dynamics following ICOS (inducible T-cell co-stimulator) agonist antibody treatment alone and in combination with PD-1 blocking antibody in a model of mammary carcinoma. PROCEDURES: Female BALB/c mice with established EMT6 tumors received 10 µg, IP of either IgG control antibodies, ICOS agonist monotherapy, or ICOS/PD-1 combination therapy on days 0, 3, 5, 7, 9, 10, or 14. Imaging was performed at 24 and 48 h post IV dose of 89Zr IAB42M1-14. In addition to 89Zr-IAB42M1-14 uptake in tumor and tumor-draining lymph node (TDLN), 3D radiomic features were extracted from PET/CT images to identify treatment effects. Imaging mass cytometry (IMC) and immunohistochemistry (IHC) was performed at end of study. RESULTS: 89Zr-IAB42M1-14 uptake in the tumor was observed by day 11 and was preceded by an increase in the TDLN as early as day 4. The spatial distribution of 89Zr-IAB42M1-14 was more uniform in the drug treated vs. control tumors, which had spatially distinct tracer uptake in the periphery relative to the core of the tumor. IMC analysis showed an increased percentage of cytotoxic T cells in the ICOS monotherapy and ICOS/PD-1 combination group compared to IgG controls. Additionally, temporal radiomics analysis demonstrated early predictiveness of imaging features. CONCLUSION: To our knowledge, this is the first detailed description of the use of a novel immune-PET imaging technique to assess the kinetics of CD8+ T-cell infiltration into tumor and lymphoid tissues following ICOS agonist and PD-1 blocking antibody therapy. By demonstrating the capacity for increased spatial and temporal resolution of CD8+ T-cell infiltration across tumors and lymphoid tissues, these observations underscore the widespread potential clinical utility of non-invasive PET imaging for T-cell-based immunotherapy in cancer.

Clinical accuracy of the AAPOS pediatric vision screening referral criteria.

BACKGROUND: The American Association for Pediatric Ophthalmology and Strabismus (AAPOS) referral criteria for amblyogenic risk factors are consensus criteria that were determined by the best-available data as well as survey results of pediatric ophthalmologists. In 2003 the AAPOS Vision Screening Committee published guidelines to standardize reporting the ability of vision screening devices to detect these factors. We attempted to assess the accuracy of the AAPOS referral criteria. METHODS: Billing records of one pediatric ophthalmologist were reviewed to identify all children who were seen in 2002. Records were excluded if photoscreening had not been performed at the initial visit or if photoscreening results were not available in the record. Of the remaining records, one-half were randomly selected for analysis. Cycloplegic refraction and binocular alignment were evaluated to determine whether the child would have been considered to be at risk for amblyopia on the basis of AAPOS referral critera. The sensitivity and specificity of these factors for detecting amblyopia was then determined. RESULTS: A total of 1,575 records were identified, of which 529 were randomly selected; 7 were excluded for incomplete data. AAPOS referral criteria would have referred 266 patients, of whom 255 had amblyopia and 11 did not; of the 256 patients who would not have been referred, 46 had amblyopia and 210 did not. In this population, the AAPOS referral criteria would have had an 85% sensitivity, 95% specificity, a 5% false-positive rate and a 15% false-negative rate for detecting amblyopia. CONCLUSIONS: Application of the AAPOS referral criteria resulted in underreporting of amblyopia in this study. We propose modifications that may result in increased sensitivity and a lower false-negative rate.