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.
Highlights
Increased understanding of the immunobiology of cancers has led to development of immune checkpoint inhibitors such as ipilimumab, pembrolizumab, and nivolumab in advanced melanoma
Early tumor infiltration by CTL may manifest as pseudo-progression presenting as transient tumor enlargement followed by tumor regression [1]
Our work has focused on the search of a reliable imaging probe for non-invasive in vivo imaging of TIL [11,12,13]
Summary
Increased understanding of the immunobiology of cancers has led to development of immune checkpoint inhibitors (anti-CTLA4 and/or anti-PD1) such as ipilimumab, pembrolizumab, and nivolumab in advanced melanoma. We present the results of a pilot clinical trial designed to examine the safety and feasibility of 99mTcHYNIC-IL2 SPECT/CT imaging and to examine the changes in TIL content of sites of metastatic melanoma in patients undergoing therapy with immune checkpoint inhibitors These data will inform the development of studies to assess the ability of 99mTc-HYNIC-IL2 SPECT/ CT imaging to distinguish true progression from pseudoprogression, RESULTS. Patient #5 underwent a pre-IO therapy biopsy of a tumor lesion with an SUV value of 0.1 (no tracer uptake), with a tissue biopsy demonstrating diffuse TIL involvement throughout the sampled tumor tissue (predominantly CD3+ cells) This unexpected result may represent a lack of IL2 receptor expression of the TIL suggesting a state of inactivation, possibly explaining the growing tumor mass in the context of TIL. Patient #5 refused week 12 reimaging due to IO treatment related side effects
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