Non-invasive visualization of tumor infiltrating lymphocytes in patients with metastatic melanoma undergoing immune checkpoint inhibitor therapy: a pilot study

Abstract

Early in the course of immunotherapy there is frequently a transient enlargement of tumor masses (pseudo-progression) due to tumor infiltration by TILs. Current clinical imaging modalities are not able to distinguished pseudo-progression from true tumor progression. Thus, patients often remain on treatment 4-8 weeks longer to confirm disease progression. Nuclear medicine offers the possibility to image immune cells and potentially discriminate pseudo-progression and progression.We conducted a pilot study in patients with metastatic melanoma receiving ipilimumab (IPI) or pembrolizumab (PEMBRO) to assess safety and feasibility of SPECT/CT imaging with 99mTc- interleukin-2 (99mTc-HYNIC-IL2) to detect TILs and distinguish between true progression from pseudo- progression. Scans were performed prior to and after 12w treatment. After labelling,99mTc-HYNIC-IL2 was purified and diluted in 10 mL of 5% glucose with 0.1% human serum albumin.Of the 5 patients (2 treated with IPI and 3 with PEMBRO) enrolled, two failed to complete the second scan as they discontinued IPI due grade 3 colitis (1 patient) or patient refusal after developing multiple toxicities attributed to IPI (1 patient). Following the first scan, one patient reported to have a grade 1 pruritus with grade 1 pain. No other toxicities attributed to the radiopharmaceutical infusion were reported. Metastatic lesions could be visualized by 99mTc-IL2 imaging and there was positive correlation between size and 99mTc-HYNIC-IL2 uptake, both before and after 12 weeks of therapy.The results of this pilot study demonstrate the safety and feasibility of 99mTc-IL2 imaging and has led to a number of hypotheses to be tested in future studies.

Development and Evaluation of Interleukin-2–Derived Radiotracers for PET Imaging of T Cells in Mice

“…Previous SPECT and PET imaging studies have shown that IL2-derived tracers could detect T-cells in inflammatory and infectious diseases, as well as different tumor types (7)(8)(9)(23)(24)(25)(26)(27)(28). In a small clinical pilot study in only five patients with melanoma, 99m Tc-IL2 SPECT could detect metastases (29). Currently, also other tracers targeting immune cells are being developed, such as targeting T-cells via CD8 specific tracers (30)(31)(32)(33).…”

Relevance of immune cell and tumor microenvironment imaging in the new era of immunotherapy

“…Therefore, radioactive IL-2 as a radiopharmaceutical to target T cells in vivo has been pioneered by Signore et al in many autoimmune pathologies. A recent study, conducted in patients affected by metastatic melanoma and undergoing immunotherapy with either pembrolizumab or ipilimumab, demonstrated the feasibility of its use as a candidate-imaging tool to evaluate TILs into tumors [162]. Indeed, in some patients, lesions with high SUV at the pre-therapy scan positively responded to the therapy.…”

Immunotherapy by Immune Checkpoint Inhibitors and Nuclear Medicine Imaging: Current and Future Applications

“…However, if the ratio between the tumor uptake and blood pool at 2 h was significantly correlated to the PD-L1 immunohistochemistry (ρ = 0.68, p = 0.014) and the uptake ratio was lower in tumors with ≤1% PD-L1 expression (1.89 versus 2.49, p = 0.048), the results seem too limited to be used in clinical practice [45]. Another radiotracer for a gamma camera is 99m Tc-interleukin-2 ( 99m Tc-IL2), which could be used to detect TILs and distinguish between true progression and pseudoprogression [46]. A pilot study has demonstrated the safety and feasibility of 99m Tc-IL2 imaging, but further studies are needed [46].…”

“…Another radiotracer for a gamma camera is 99m Tc-interleukin-2 ( 99m Tc-IL2), which could be used to detect TILs and distinguish between true progression and pseudoprogression [46]. A pilot study has demonstrated the safety and feasibility of 99m Tc-IL2 imaging, but further studies are needed [46].…”