Abstract LB037: 89ZED88082A PET imaging to visualize CD8+ T cells in patients with cancer treated with immune checkpoint inhibitor

Abstract

T cell enhancing immune checkpoint inhibitors (ICI) are effective across several tumor types in a subset of patients. Insights into systemic localization of cytotoxic CD8+ T cells might support early treatment decisions. To address this, we performed a PET imaging study with a zirconium-89 (89Zr) labeled one-armed CD8-specific antibody 89ZED88082A to assess tracer performance, safety, and pharmacokinetics (PK) before and during treatment. Here we report preliminary data on uptake in tumor lesions before ICI. Methods: Patients with locally advanced or metastatic solid tumors that may benefit from ICI are eligible. In part A (imaging before treatment) and part B (imaging before and during treatment), 37 MBq (1 mCi) 89ZED88082A is administered with unlabeled one-armed antibody CED88004S to vary total protein dose. PET images are acquired at up to 4 time points: 1 h, and days (d) 2, 4, 7 post-injection followed by a tumor biopsy for CD8 immunohistochemistry and autoradiography (NCT04029181). Subsequently, patients receive atezolizumab (NCT02478099) or standard of care nivolumab ± ipilimumab. Tumor and lymph node 89ZED88082A uptake are assessed as (geometric mean) maximum standard uptake value (SUVmax), in other organs as SUVmean. Serum 89ZED88082A/CED88004S levels are measured for PK. Tumor response is according to (i)RECIST1.1. Results: For pretreatment imaging results, 32 patients (9 part A, 23 part B) were evaluable; 3 received 4 mg total tracer protein dose, 29 received 10 mg. No tracer infusion-related reactions occurred. Here we show results on d2 PET imaging with 10 mg protein dose, which was considered optimal based on superior 89Zr blood pool activity, clinical feasibility and serum antibody PK with a half-life of 28.6 h. 89ZED88082A uptake was observed within 1 h in spleen, and strong d2 imaging signal was seen across lymphoid organs including spleen (\bar{x}$ SUVmean 47.2), lymph nodes (SUVmax 4.2), bone marrow (\bar{x}$ SUVmean 5.0), small bowel and Waldeyer's ring. 89ZED88082A tumor uptake was seen at all main metastatic organ sites (overall lesion SUVmax 5.5, range 0.6-30.9) and varied across patients (\bar{x}$ per patient SUVmax 5.4, IQR 3.8-7.4). Higher tumor uptake showed a trend with better response (p=0.059) and longer PFS (p=0.033). Tumor uptake was higher in patients with mismatch-repair deficient (dMMR) than MMR proficient tumors (SUVmax 9.3 vs 4.9, p<0.001). Tumors with immune desert vs CD8+ cell stromal/inflamed profile had a \bar{x}$ SUVmax of 4.7 vs 8.3 (p=0.042). In tumor biopsies, autoradiography signal and CD8 staining were linearly associated (p<0.001). Conclusion: 89ZED88082A PET imaging is safe and shows high uptake in normal lymphoid organs. Uptake in tumor lesions is heterogeneous within and between patients. Tumor uptake is higher pretreatment in dMMR tumors and correlated with patient outcome. 89ZED88082A uptake on PET and by autoradiography reflects CD8 expression in tumor biopsies. Citation Format: Laura Kist de Ruijter, Pim P. van de Donk, Jahlisa S. Hooiveld-Noeken, Danique Giesen, Alexander Ungewickell, Bernard M. Fine, Simon P. Williams, Sandra M. Sanabria Bohorquez, Mahesh Yadav, Hartmut Koeppen, Jing Jing, Sebastian Guelman, Mark T. Lin, Michael J. Mamounas, Jeffrey Eastham, Patrick K. Kimes, Andor W. Glaudemans, Adrienne H. Brouwers, Marjolijn N. Lub-de Hooge, Jourik A. Gietema, Carolina P. Schröder, Wim Timens, Mathilde Jalving, Sjoerd Elias, Sjoukje F. Oosting, Derk J. de Groot, Elisabeth G. de Vries. 89ZED88082A PET imaging to visualize CD8+ T cells in patients with cancer treated with immune checkpoint inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB037.

CD8-targeted PET Imaging of Tumor Infiltrating T cells in Patients with Cancer: A Phase I First-in-Human Study of 89Zr-Df-IAB22M2C, a Radiolabeled anti-CD8 Minibody

“…However, these probes do not specifically target the immune system, so changes in organ and tumor uptake can be difficult to interpret. Recently, the results from a PET imaging trial with 89 ZED88082A, a CD8-targeted probe, were presented ( 33 ). 89 ZED88082A demonstrated uptake in the spleen, lymph nodes, and bone marrow similar to that of 89 Zr-Df-IAB22M2C; however, comparison of tumor uptake is difficult given differences in patient populations.…”

18F FDG PET/CT and Novel Molecular Imaging for Directing Immunotherapy in Cancer

“…Heterogeneity of immune response within and between lesions presents a further test with an ever-increasing number of combinational systemic and/or modality therapies. Safe, uptake in normal lymphoid organs (SUVmean), inter-tumoral heterogeneity demonstrated, higher pretreatment uptake in dMMR vs MMR proficient tumors (SUVmax 9.3 vs 4.9, p<0.001) with higher SUVmax showing trend toward improved immunotherapy response (p=0.059), high SUVmax was associated with a CD8+ stromal/inflamed profile (p=0.042) [101] This table summarizes the reported clinical radiopharmaceutical imaging studies of immune targets in cancer. Abbreviations: AMT --methyl-ltryptophan; AUCarea under the curve; CIconfidence interval; CRCcolorectal cancer; CTLA-4cytotoxic T-lymphocyte associated protein 4;…”

“…As such, in vivo CD8+ T cell imaging can help define the TME, particularly in respect to CPI resistance, where high levels of PD-L1 may not be associated with anti-PD-(L)1 therapy response if cytotoxic T cells are unable to infiltrate or function in an immunosuppressive environment. CD8+ specific radiopharmaceutical 89 ZED88082A uptake was shown in a study of 32 patients with solid tumors to correlate with CD8+ on immunohistochemistry and with response to CPI [101]. Further clinical studies are underway, such as CD8+ directed ⁸⁹Zr-IAB22M2C and activated T cell targeting [ 18 F]-F-AraG PET (Suppl.…”

Molecular imaging to support cancer immunotherapy

“…Furthermore, higher tracer uptake in tumor lesions at baseline showed a trend with improved clinical outcomes. 63 Serial CD8 PET imaging results for both tracers are not yet available. The third CD8 PET tracer currently being investigated is [ 68 Ga]Ga-NODAGA-SNA006 (NCT05126927).…”