Background: Novel imaging modalities using frequently expressed RCC antigens, such as CAIX, have shown promise in early-stage disease (Shuch B et al ASCO GU 2023). In advanced RCC, no tissue-based biomarkers have been well established to predict outcome with contemporary regimens, e.g., checkpoint inhibitors (CPIs) or targeted therapy (TT). We hypothesize that functional imaging of CD8 T-cells (CD8s) with crefmirlimab (a ~80 kDA ⁸⁹Zr-labelled minibody with high affinity for CD8) may predict response given the essential role of CD8T-cells (CD8s) in mediating CPI response. Methods: Eligible pts had pathologically verified RCC, metastatic disease and an intent to initiate standard of care CPI therapy. Patients received crefmirlimab PET/CT within 1 wk of CPI infusion and 4-6 weeks after initiating therapy. Baseline biopsy was mandated, along with repeat biopsy 0-2 weeks following the second PET/CT scan. PET signal was characterized as SUV_max, SUV_peak and SUV_mean of the biopsied lesions, up to 5 index lesions and representative CD8 avid lymph nodes. Mean SUV_max in responders and non-responders were compared using students t-test (1-sided). CD8 expression in tissue was characterized as the number of positive cells per mm²; PET avidity and CD8 expression were compared using the Spearman correlation coefficient. Results: 17 pts (9 M: 8 F) were enrolled; most pts had clear cell histology (12; 71%) followed by unclassified (3; 17%) and papillary (2; 12%). The most commonly rendered CPI-based regimens were nivolumab alone (6 pts; 35%) and cabozantinib/nivolumab (3 pts; 17%). Follow-up data was available in 15 of the patients. By RECIST v1.1, 3 of 15 patients were classified as responders (best overall response [BOR] of complete response or partial response) and 12 patients were classified as non-responders (BOR of stable disease or progressive disease). Average SUV_max, SUV_peak and SUV_mean per patientamong all quantified index lesions and representative lymph nodes were 10.02, 6.95 and 6.11 for baseline and 8.82, 6.23 and 5.39 during treatment, respectively. Average SUV_max at baseline was 14.68 in responders to CPI and 8.28 in non-responders (P=0.006). On treatment SUV_max was 10.93 in responders to CPI and 8.22 in non-responders (P=0.19). A strong correlation between CD8 expression in baseline tissue and normalized SUV_mean was observed (r=0.77; 95%CI 0.53-0.91). Conclusions: To our knowledge, this is the first series in RCC to demonstrate that functional imaging of immune cells (here, CD8s) may segregate response to CPIs, with responders having a higher baseline SUV and a larger decrement in SUV with therapy. Our results are bolstered by a significant correlation between tissue and imaging CD8 expression. Larger studies are underway to validate this noninvasive strategy. Clinical trial information: NCT03802123.