¹⁸F-FAraG PET for CD8 Profiling of Tumors and Assessment of Immunomodulation by Chemotherapy

Abstract

Majority of the clinical trials exploring various combinations of chemo- and immunotherapy rely on serial biopsy to provide information on immune response. The aim of this study was to assess the value of ¹⁸F-FAraG as a non-invasive tool that could profile tumors based on the key players in adaptive antitumor response, CD8+ cells, and evaluate immunomodulatory effects of chemotherapy. Methods: To evaluate the ability of ¹⁸F-FAraG to report on the presence of CD8+ cells within the TME, we imaged a panel of syngeneic tumor models (MC38, CT26, LLC, A9F1, 4T1 and B16F10), and correlated the signal intensity with the number of lymphocytes found in the tumors. The capacity of ¹⁸F-FAraG to detect immunomodulatory effects of chemotherapy, was determined by longitudinal imaging of tumor bearing mice (MC38, A9F1) undergoing two types of chemotherapy: oxaliplatin/cyclophosphamide, shown to induce immunogenic cell death and paclitaxel/carboplatin, reported to cause immunogenically silent tumor cell death. Results: ¹⁸F-FAraG revealed strikingly different uptake patterns in the tumor panel, which resembled cancer-immune phenotypes observed in the clinic. Statistically significant correlation was found between the ¹⁸F-FAraG signal and the number of PD-1 positive CD8+ cells isolated from the tumors (r2=0.528, p<0.0001). In the MC38 model, paclitaxel/carboplatin did not result in appreciable change in signal post therapy (1.69 ± 0.25 vs. 1.50 ± 0.33 %ID/g), but oxaliplatin/cyclophosphamide treatment led to close to 2.4 fold higher ¹⁸F-FAraG signal (1.20 ± 0.31 vs. 2.84 ± 0.93 %ID/g). The statistically significant increase in signal post oxaliplatin/cyclophosphamide was also observed in A9F1 model (0.95 ± 0.36 vs.1.99 ± 0.54 %ID/g). Conclusion: The ability of ¹⁸F-FAraG PET to assess the location and function of CD8+ cells, as well immune activity within tumors post immune priming therapy warrants further investigation into its utility for patient selection, evaluation of optimal time to deliver immunotherapies, and assessment of combinatorial therapy approaches.