89Zr-pembrolizumab imaging as a non-invasive approach to assess clinical response to PD-1 blockade in cancer

Abstract

Background: Programmed cell death protein 1 (PD-1) antibody treatment is standard of care for melanoma and nonsmall-cell lung cancer (NSCLC). Accurately predicting which patients will benefit is currently not possible. Tumor uptake and biodistribution of the PD-1 antibody might play a role. Therefore, we carried out a positron emission tomography (PET) imaging study with zirconium-89 ( 89 Zr)-labeled pembrolizumab before PD-1 antibody treatment. Patients and methods: Patients with advanced or metastatic melanoma or NSCLC received 37 MBq (1 mCi) 89 Zrpembrolizumab (w2.5 mg antibody) intravenously plus 2.5 or 7.5 mg unlabeled pembrolizumab. After that, up to three PET scans were carried out on days 2, 4, and 7. Next, PD-1 antibody treatment was initiated. 89 Zrpembrolizumab tumor uptake was calculated as maximum standardized uptake value (SUV max ) and expressed as geometric mean. Normal organ uptake was calculated as SUV mean and expressed as a mean. Tumor response was assessed according to (i)RECIST v1.1. Results: Eighteen patients, 11 with melanoma and 7 with NSCLC, were included. The optimal dose was 5 mg pembrolizumab, and the optimal time point for PET scanning was day 7. The tumor SUV max did not differ between melanoma and NSCLC (4.9 and 6.5, P ¼ 0.49). Tumor 89 Zr-pembrolizumab uptake correlated with tumor response (P trend ¼ 0.014) and progression-free (P ¼ 0.0025) and overall survival (P ¼ 0.026). 89 Zr-pembrolizumab uptake at 5 mg was highest in the spleen with a mean SUV mean of 5.8 (standard deviation AE1.8). There was also 89 Zr-pembrolizumab uptake in Waldeyer's ring, in normal lymph nodes, and at sites of inflammation. Conclusion: 89 Zr-pembrolizumab uptake in tumor lesions correlated with treatment response and patient survival. 89 Zrpembrolizumab also showed uptake in lymphoid tissues and at sites of inflammation.

ImmunoPET: Antibody-Based PET Imaging in Solid Tumors

“…Several preclinical studies showed favorable binding affinity and imaging of melanoma cell lines using Abs and Ab fragments targeting immune checkpoints, PD-1/PD-L1 (9,119,(340)(341)(342)(343)(344)(345) and CTLA-4 (346). However, the uptake in the lymphoid tissue was also high (119,347). Moreover, radiotherapy-induced PD-L1 upregulation was demonstrated in melanoma mouse models, using radiolabeled anti-PD-L1 Abs (348,349).…”

“…Another immune checkpoint, T-cell immunoglobulin and mucin domain-containing-3 (TIM-3), was a successful target for murine melanoma models ( 97 ). One clinical study evaluated [ 89 Zr]Zr-pembrolizumab in melanoma, reporting relations between tracer uptake and response to therapy and survival in patients with advanced or metastatic disease ( 347 ). Also, an ongoing phase II clinical trial is investigating the biodistribution and tumor uptake of [ 89 Zr]Zr-ipilimumab (anti-CTLA-4) in advanced melanoma (NCT03313323).…”

Radionuclide imaging and therapy directed towards the tumor microenvironment: a multi-cancer approach for personalized medicine

“…In addition, anti-PD-1 antibodies, including 89 Zr-labeled pembrolizumab and nivolumab, have been evaluated. Clinical trials in melanoma and non-small cell lung cancer patients showed that the uptake of both these radioligands correlates with patient responses to anti-PD-1 checkpoint inhibition therapy with their corresponding inhibitor [175,176]. Notably, studies showed that the level of PDL1 expression determined by immunohistochemistry does not accurately predict the response to therapy.…”

Current state and upcoming opportunities for immunoPET biomarkers in lung cancer

“…Additionally, no relation was found between tracer uptake and PD-1 expression, as seen by IHC. In a comparable study, Kok et al (2022) evaluated the response to pembrolizumab monotherapy or a nivolumab plus ipilimumab therapy with 89 Zr-pembrolizumab for patients with NSCLC or melanoma [19]. A significant correlation was found between tracer tumor uptake and clinical Fig.…”