45 AI-assisted whole-body assessment of immunotherapy response using [18F]F-AraG, a PET agent for activated T cells

Abstract

BackgroundPatterns of response to immunotherapy differ from traditional cytotoxic drugs, making clinical decisions concerning response evaluation more challenging. Radiological response criteria, such as iRECIST, updated to address response patterns unique to immunotherapeutics, focus only on changes in the tumor burden.1 An 18F labeled nucleoside analog, [18F]F-AraG was developed as a PET agent for imaging activated T cells,2–5 critical components of immune response and the common target of immunotherapies. Whole body assessment of [18F]F-AraG uptake that indicates presence of activated T cells might allow for analysis of complex immunologic processes and provide early indication of treatment response as well as off-target side effects. Here, we employ AIQ Solutions’ TRAQinform IQ software to analyze [18F]F-AraG scans and assess activation of T cells in head and neck squamous cell carcinoma (HNSCC) patients undergoing anti-PD-1 therapy.MethodsFour treatment-naïve HNSCC patients were imaged using [18F]F-AraG before and 2–3 weeks after a single dose of anti-PD-1 antibody. [18F]F-AraG PET scans of six healthy subjects were used to define areas of increased [18F]F-AraG uptake in patients. The regions of uptake in the baseline and on-treatment scans were registered and matched using articulated registration.6 7 Standardized uptake values, SUVmax, SUVmean and SUVtotal were extracted from all areas of tracer uptake in both scans and changes in signal calculated to assess therapy effects. The change in signal was analyzed in the context of the patient‘s clinical status and changes in T cell infiltration in the primary lesion when biopsy specimens were available.ResultsTRAQinform IQ whole body evaluation of [18F]F-AraG PET revealed heterogeneity in the signal range and extent of signal change both between different patients and between different areas of tracer uptake within the same patient (figure 1). The post-therapy whole-body [18F]F-AraG signal change trended with patients‘ outcome. The patients with areas where the signal disappeared or decreased post therapy, indicative of the lack of T cell activation, had shorter overall survival than the patients with areas with stable and increasing signal. The change in infiltration of activated T cells in the primary lesion tissue did not correspond to the patient survival, reflecting limitations of serial biopsy in evaluating therapy response.Abstract 45 Figure 1TRAQinform IQ assessment of the SUVmean [18F]F-AraG signal change in a HNSCC patient two weeks after a single dose of anti-PD-1 antibody. Quantification of the differences in the [18F]F-AraG uptake in the baseline and on-treatment scan revealed 17 hotspots with disappearing or decreasing signal, 22 hotpots with the stable signal and 11 hotspots with increasing or new signal post therapy.ConclusionsTRAQinform IQ analysis and quantification of [18F]F-AraG PET provides patient-level assessment of tracer uptake and may allow for better understanding of heterogeneity of T cell activation and potentially offer a more comprehensive evaluation of response to immunotherapy than the standard, tumor-centric, radiologic methods.ReferencesNishino M, et al. Monitoring immune-checkpoint blockade: response evaluation and biomarker development. Nat Rev Clin Oncol, 2017.Namavari M, et al. Synthesis of 2’-deoxy-2’-[18F]fluoro-9-beta-D-arabinofuranosylguanine: a novel agent for imaging T-cell activation with PET. Mol Imaging Biol 2011; 13(5):812–8.Ronald JA, et al. A PET imaging strategy to visualize activated T cells in acute graft-versus-host disease elicited by allogenic hematopoietic cell transplant. Cancer Res 2017; 77(11):2893–2902.Levi J, et al. Imaging of activated T cells as an early predictor of immune response to anti-PD-1 Therapy. Cancer Research 2019; 79(13):3455–3465.Levi J, et al. (18)F-AraG PET for CD8 profiling of tumors and assessment of immunomodulation by chemotherapy. J Nucl Med 2021; 62(6):802–807.Yip S, T Perk, and R Jeraj, Development and evaluation of an articulated registration algorithm for human skeleton registration. Phys Med Biol 2014; 59(6):1485–99.Yip S. and R Jeraj. Use of articulated registration for response assessment of individual metastatic bone lesions. Phys Med Biol 2014; 59(6): 1501–14.Ethics ApprovalThe study was approved by Stanford University Ethics Board, approval number 40425.

Clinical Application of ImmunoPET Targeting Checkpoint Inhibitors

“…Furthermore, a change in the [ 18 F]F-AraG signal predicted the clinical outcome, as demonstrated in a recent AI-assisted whole-body evaluation of four SCCHN patients were imaged using [ 18 F]F-AraG before and 2-3 weeks after a single dose of an anti-PD-1 antibody. Patients with areas of stable or increasing signals post-therapy had a longer survival than patients where the signal disappeared or decreased post-therapy, indicative of the lack of T-cell activation [51]. An ongoing phase 2 trial (NCT04401995) is further analyzing tracers in melanoma patients treated with the TLR9 agonist vidutolimod (CMP-001) in combination with nivolumab vs. nivolumab alone.…”

The other immuno-PET: Metabolic tracers in evaluation of immune responses to immune checkpoint inhibitor therapy for solid tumors

“…The ability of [ 18 F]F-AraG to image T cells activation and thus provide early indication of adaptive response to immunotherapies in cancer patients is currently being investigated in multiple Phase II trials. An AI-assisted whole body evaluation of the change in [ 18 F]F-AraG signal in four head and neck squamous cell carcinoma (HNSCC) patients after a single dose of anti-PD-1 antibody, revealed both inter and intra-patient heterogeneity in immune response to therapy ( 55 ). Importantly, the change in [ 18 F]F-AraG signal trended with the clinical outcome.…”

“…In addition, the dynamic nature of T cell recruitment and activation makes it important to optimize time of imaging after the start of therapy. Given these characteristics of T cells, signal quantification metrics other than the most commonly used, SUV max need to be investigated ( 55 ). A closer look into the SUV peak , SUV mean , SUV based heterogeneity index, metabolic volume of the radiotracer, total lesion metabolic uptake, SLR or BLR, may be necessary to further understand the utility of metabolic radiotracers in immunotherapy.…”