Development, Characterization, and Radiation Dosimetry Studies of 18F-BMS-986229, a 18F-Labeled PD-L1 Macrocyclic Peptide PET Tracer.

PURPOSE: In cancer immunotherapy, the blockade of the interaction between programmed death-1 and its ligand (PD-1:PD-L1) has proven to be one of the most promising strategies. However, as mechanisms of resistance to PD-1/PD-L1 inhibition include variability in tumor cell PD-L1 expression in addition to standard tumor biopsy PD-L1 immunohistochemistry (IHC), a comprehensive and quantitative approach for measuring PD-L1 expression is required. Herein, we report the development and characterization of an 18F-PD-L1-binding macrocyclic peptide as a PET tracer for the comprehensive evaluation of tumor PD-L1 expression in cancer patients. PROCEDURES: 18F-BMS-986229 was characterized for PD-L1 expression assessment by autoradiography or PET imaging. 18F-BMS-986229 was utilized to evaluate tumor PD-L1 target engagement in competition with a macrocyclic peptide inhibitor of PD-L1 (BMS-986189) over a range of doses using PET imaging. A whole-body radiation dosimetry study of 18F-BMS-986229 in healthy non-human primates (NHPs) was performed. RESULTS: In vitro autoradiography showed an 8:1 binding ratio in L2987(PD-L1 +) vs. HT-29 (PD-L1-) tumors, more than 90% of which could be blocked with 1 nM of BMS-986189. Ex vivo autoradiography showed that 18F-BMS-986229 detection was penetrant over a series of sections spanning the entire L2987 tumor. In vivo PET imaging in mice demonstrated a 5:1 tracer uptake ratio (at 90-100 min after tracer administration) in L2987 vs. HT-29 tumors and demonstrated 83%-93% specific binding of BMS-986189 within those dose ranges. In a healthy NHP dosimetry study, the resultant whole-body effective dose was 0.025 mSv/MBq. CONCLUSION: 18F-BMS-986229 has been preclinically characterized and exhibits high target specificity, low background uptake, and a short blood half-life supportive of same day imaging in the clinic. As the PET tracer, 18F-BMS-986229 shows promise in the quantification of PD-L1 expression, and its use in monitoring longitudinal changes in patients may provide insights into PD-1:PD-L1 immuno-therapy treatment outcomes.

Systemic and Intracranial Outcomes With First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC and Baseline Brain Metastases From CheckMate 227 Part 1.

INTRODUCTION: In CheckMate 227 Part 1, nivolumab plus ipilimumab prolonged overall survival (OS) versus chemotherapy in patients with metastatic NSCLC, regardless of tumor programmed death-ligand 1 (PD-L1) expression. Here, we report post hoc exploratory systemic and intracranial efficacy outcomes and safety by baseline brain metastasis status at 5 years' minimum follow-up. METHODS: Treatment-naive adults with stage IV or recurrent NSCLC without EGFR or ALK alterations, including asymptomatic patients with treated brain metastases, were enrolled. Patients with tumor PD-L1 greater than or equal to 1% were randomized to nivolumab plus ipilimumab, nivolumab, or chemotherapy; patients with tumor PD-L1 less than 1% were randomized to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy groups. Assessments included OS, systemic and intracranial progression-free survival per blinded independent central review, new brain lesion development, and safety. Brain imaging was performed at baseline (all randomized patients) and approximately every 12 weeks thereafter (patients with baseline brain metastases only). RESULTS: Overall, 202 of 1739 randomized patients had baseline brain metastases (nivolumab plus ipilimumab: 68; chemotherapy: 66). At 61.3 months' minimum follow-up, nivolumab plus ipilimumab prolonged OS versus chemotherapy in patients with baseline brain metastases (hazard ratio = 0.63; 95% confidence interval: 0.43-0.92) and in those without (hazard ratio = 0.76; 95% confidence interval: 0.66-0.87). In patients with baseline brain metastases, 5-year systemic and intracranial progression-free survival rates were higher with nivolumab plus ipilimumab (12% and 16%, respectively) than chemotherapy (0% and 6%). Fewer patients with baseline brain metastases developed new brain lesions with nivolumab plus ipilimumab (4%) versus chemotherapy (20%). No new safety signals were observed. CONCLUSIONS: With all patients off immunotherapy for more than or equal to 3 years, nivolumab plus ipilimumab continued to provide a long-term, durable survival benefit in patients with or without brain metastases. Intracranial efficacy outcomes favored nivolumab plus ipilimumab versus chemotherapy. These results further support nivolumab plus ipilimumab as an efficacious first-line treatment for patients with metastatic NSCLC, regardless of baseline brain metastasis status.

Optical techniques for the intraoperative assessment of nodal status.

The lymphatic system is an important pathway in the metastatic spread of many malignancies and a key prognostic indicator. Nondestructive assessment of the nodal status during surgery could limit the amount of lymph nodes that need to be resected and allow for immediate regional lymphadenectomy during sentinel lymph node biopsy procedures. This review looks into the possibilities of conventional medical imaging methods that are capable of intraoperative nodal assessment and discusses multiple newly developed optical techniques. The physical background behind these techniques is reviewed and a concise overview of their main advantages and disadvantages is provided. These recent innovations show that while the application of optical modalities for intraoperative nodal staging is not yet applied routinely, there is reason enough to expect their introduction in the near future.

Intra-operative ex vivo photoacoustic nodal staging in a rat model using a clinical superparamagnetic iron oxide nanoparticle dispersion.

The ability to accurately detect tumor metastases in lymph nodes is essential for intra-operative staging of various malignancies. Histopathological assessment of nodes has the drawback of a time delay before results are available to the surgeon and a likelihood of missing metastases. Photoacoustic (PA) imaging has been shown to possess the potential to detect melanoma metastases in resected in toto lymph nodes based on intrinsic contrast. To extend application of the method to other malignancies, extrinsic contrast for lymphatic mapping is important. We investigate in a metastatic animal model whether clinically approved superparamagnetic iron oxide (SPIO) nanoparticles, applied for MRI, can help PA imaging for staging in an intra-operative ex vivo setting. Imaging results are compared with 14 Tesla MR images and histology. We observe that irregularities in SPIO distribution in PA images of the nodes and a decrease in contrast correlate with metastatic involvement as seen in MR images and histology. The results show that a PA based imaging technique may be valuable for nodal staging in the field of surgical oncology.

Evaluation of superparamagnetic iron oxide nanoparticles (Endorem®) as a photoacoustic contrast agent for intra-operative nodal staging.

Detection of tumor metastases in the lymphatic system is essential for accurate staging of malignancies. Commercially available superparagmagnetic nanoparticles (SPIOs) accumulate in normal lymph tissue after injection at a tumor site, whereas less or no accumulation takes place in metastatic nodes, thus enabling lymphatic staging using MRI. We verify for the first time the potential of SPIOs, such as Endorem(®) as a novel photoacoustic (PA) contrast agent in biological tissue. We injected five Wistar rats subcutaneously with variable amounts of Endorem(®) and scanned the resected lymph nodes using a tomographic PA setup. Findings were compared using histology, vibrating sample magnetometry (VSM) and 14 T MR-imaging. Our PA setup was able to detect the iron oxide accumulations in all the nodes containing the nanoparticles. The distribution inside the nodes corresponded with both MRI and histological findings. VSM revealed that iron quantities inside the nodes varied between 51 ± 4 and 11 ± 1 µg. Nodes without SPIO enhancement did not show up in any of the PA scans. Iron oxide nanoparticles (Endorem(®)) can be used as a PA contrast agent for lymph node analysis and a distinction can be made between nodes with and nodes without the agent. This opens up possibilities for intra-operative nodal staging for patients undergoing nodal resections for metastatic malignancies.

Initial results of imaging melanoma metastasis in resected human lymph nodes using photoacoustic computed tomography.

The pathological status of the sentinel lymph node is important for accurate melanoma staging, ascertaining prognosis and planning treatment. The standard procedure involves biopsy of the node and histopathological assessment of its status. Drawbacks of this examination include a finite sampling of the node with the likelihood of missing metastases, and a significant time-lag before histopathological results are available to the surgeon. We studied the applicability of photoacoustic computed tomographic imaging as an intraoperative modality for examining the status of resected human sentinel lymph nodes. We first applied the technique to image ex vivo pig lymph nodes carrying metastases-simulating melanoma cells using multiple wavelengths. The experience gained was applied to image a suspect human lymph node. We validated the photoacoustic imaging results by comparing a reconstructed slice with a histopathological section through the node. Our results suggest that photoacoustics has the potential to develop into an intraoperative imaging method to detect melanoma metastases in sentinel lymph nodes.