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89Zr-immuno-PET using the anti-LAG-3 tracer [89Zr]Zr-BI 754111: demonstrating target specific binding in NSCLC and
Iris H C Miedema1,2, Marc C Huisman2,3, Gerben J C Zwezerijnen2,3
1Department of Medical Oncology, Amsterdam UMC location Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, the Netherlands.
Purpose:
Although lymphocyte activation gene-3 (LAG-3) directed therapies demonstrate promising clinical anti-cancer activity, only a subset of patients seems to benefit and predictive biomarkers are lacking. Here, we explored the potential use of the anti-LAG-3 antibody tracer [89Zr]Zr-BI 754111 as a predictive imaging biomarker and investigated its target specific uptake as well as the correlation of its tumor uptake and the tumor immune infiltration.
Methods:
Patients with head and neck (N = 2) or lung cancer (N = 4) were included in an imaging substudy of a phase 1 trial with BI 754091 (anti-PD-1) and BI 754111 (anti-LAG-3). After baseline tumor biopsy and [18F]FDG-PET, patients were given 240 mg of BI 754091, followed 8 days later by administration of [89Zr]Zr-BI 754111 (37 MBq, 4 mg). PET scans were performed 2 h, 96 h, and 144 h post-injection. To investigate target specificity, a second tracer administration was given two weeks later, this time with pre-administration of 40 (N = 3) or 600 mg (N = 3) unlabeled BI 754111, followed by PET scans at 96 h and 144 h post-injection. Tumor immune cell infiltration was assessed by immunohistochemistry and RNA sequencing.
Results:
Tracer uptake in tumors was clearly visible at the 4-mg mass dose (tumor-to-plasma ratio 1.63 [IQR 0.37-2.89]) and could be saturated by increasing mass doses (44 mg: 0.67 [IQR 0.50-0.85]; 604 mg: 0.56 [IQR 0.42-0.75]), demonstrating target specificity. Tumor uptake correlated to immune cell-derived RNA signatures.
Conclusions:
[89Zr]Zr-BI-754111 PET imaging shows favorable technical and biological characteristics for developing a potential predictive imaging biomarker for LAG-3-directed therapies.
Trial Registration:
ClinicalTrials.gov , NCT03780725. Registered 19 December 2018.
Insights
The novel imaging tracer [89Zr]Zr-BI 754111 shows promise as a predictive biomarker for lymphocyte-activation gene-3 (LAG-3) therapies. Its tumor uptake correlates with immune cell infiltration, aiding in patient selection for cancer treatment.
Area of Science:
- Immunotherapy
- Radiopharmaceuticals
- Oncology Imaging
Background:
- Lymphocyte-activation gene-3 (LAG-3) targeted therapies show anti-cancer potential but lack predictive biomarkers.
- Identifying patients who benefit from LAG-3 therapies is crucial for treatment efficacy.
- Current biomarkers for predicting response to immunotherapy are limited.
Purpose of the Study:
- To evaluate [89Zr]Zr-BI 754111 as a potential imaging biomarker for LAG-3-directed cancer therapies.
- To assess the target-specific uptake of the [89Zr]Zr-BI 754111 tracer in tumors.
- To investigate the correlation between tumor uptake of the tracer and tumor immune cell infiltration.
Main Methods:
- Phase 1 trial imaging substudy involving head and neck and lung cancer patients.
- Administration of anti-PD-1 (BI 754091) followed by [89Zr]Zr-BI 754111 (anti-LAG-3) tracer.
- Positron emission tomography (PET) scans at multiple time points, with and without unlabeled tracer to assess target saturation.
- Tumor immune cell infiltration analysis via immunohistochemistry and RNA sequencing.
Main Results:
- Significant tumor uptake of [89Zr]Zr-BI 754111 was observed at a 4-mg mass dose (tumor-to-plasma ratio 1.63).
- Tracer uptake demonstrated target specificity, as it was saturated by higher unlabeled tracer doses (44 mg and 600 mg).
- Tumor uptake of the tracer positively correlated with immune cell-derived RNA signatures.
Conclusions:
- The [89Zr]Zr-BI 754111 tracer exhibits favorable technical and biological characteristics for imaging.
- This tracer holds potential as a predictive imaging biomarker for patients undergoing LAG-3-directed therapies.
- Further development of [89Zr]Zr-BI 754111 PET imaging could aid in patient stratification for immunotherapy.
