Imaging with [89Zr]Zr-DFO-SC16.56 anti-DLL3 antibody in patients with high-grade neuroendocrine tumours of the lung and prostate: a phase 1/2, first-in-human trial.

BACKGROUND: Delta-like ligand 3 (DLL3) is aberrantly expressed on the surface of small-cell lung cancer (SCLC) and neuroendocrine prostate cancer cells. We assessed the safety and feasibility of the DLL3-targeted imaging tracer [89Zr]Zr-DFO-SC16.56 (composed of the anti-DLL3 antibody SC16.56 conjugated to p-SCN-Bn-deferoxamine [DFO] serving as a chelator for zirconium-89) in patients with neuroendocrine-derived cancer. METHODS: We conducted an open-label, first-in-human study of immunoPET-CT imaging with [89Zr]Zr-DFO-SC16.56. The study was done at Memorial Sloan Kettering Cancer Center, New York, NY, USA. Patients aged 18 years or older with a histologically verified neuroendocrine-derived malignancy and an Eastern Cooperative Oncology Group performance status of 0-2 were eligible. An initial cohort of patients with SCLC (cohort 1) received 37-74 MBq [89Zr]Zr-DFO-SC16.56 as a single intravenous infusion at a total mass dose of 2·5 mg and had serial PET-CT scans at 1 h, day 1, day 3, and day 7 post-injection. The primary outcomes of phase 1 of the study (cohort 1) were to estimate terminal clearance half-time, determine whole organ time-integrated activity coefficients, and assess the safety of [89Zr]Zr-DFO-SC16.56. An expansion cohort of additional patients (with SCLC, neuroendocrine prostate cancer, atypical carcinoid tumours, and non-small-cell lung cancer; cohort 2) received a single infusion of [89Zr]Zr-DFO-SC16.56 at the same activity and mass dose as in the initial cohort followed by a single PET-CT scan 3-6 days later. Retrospectively collected tumour biopsy samples were assessed for DLL3 by immunohistochemistry. The primary outcome of phase 2 of the study in cohort 2 was to determine the potential association between tumour uptake of the tracer and intratumoural DLL3 protein expression, as determined by immunohistochemistry. This study is ongoing and is registered with ClinicalTrials.gov, NCT04199741. FINDINGS: Between Feb 11, 2020, and Jan 30, 2023, 12 (67%) men and six (33%) women were enrolled, with a median age of 64 years (range 23-81). Cohort 1 included three patients and cohort 2 included 15 additional patients. Imaging of the three patients with SCLC in cohort 1 showed strong tumour-specific uptake of [89Zr]Zr-DFO-SC16.56 at day 3 and day 7 post-injection. Serum clearance was biphasic with an estimated terminal clearance half-time of 119 h (SD 31). The highest mean absorbed dose was observed in the liver (1·83 mGy/MBq [SD 0·36]), and the mean effective dose was 0·49 mSv/MBq (SD 0·10). In cohort 2, a single immunoPET-CT scan on day 3-6 post-administration could delineate DLL3-avid tumours in 12 (80%) of 15 patients. Tumoural uptake varied between and within patients, and across anatomical sites, with a wide range in maximum standardised uptake value (from 3·3 to 66·7). Tumour uptake by [89Zr]Zr-DFO-SC16.56 was congruent with DLL3 immunohistochemistry in 15 (94%) of 16 patients with evaluable tissue. Two patients with non-avid DLL3 SCLC and neuroendocrine prostate cancer by PET scan showed the lowest DLL3 expression by tumour immunohistochemistry. One (6%) of 18 patients had a grade 1 allergic reaction; no grade 2 or worse adverse events were noted in either cohort. INTERPRETATION: DLL3 PET-CT imaging of patients with neuroendocrine cancers is safe and feasible. These results show the potential utility of [89Zr]Zr-DFO-SC16.56 for non-invasive in-vivo detection of DLL3-expressing malignancies. FUNDING: National Institutes of Health, Prostate Cancer Foundation, and Scannell Foundation.

First-in-human imaging with [89Zr]Zr-DFO-SC16.56 anti-DLL3 antibody in patients with high-grade neuroendocrine tumors of the lung and prostate.

Background: Delta-like ligand 3 (DLL3) is aberrantly expressed on the cell surface in many neuroendocrine cancers including small cell lung cancer (SCLC) and neuroendocrine prostate cancer (NEPC). Several therapeutic agents targeting DLL3 are in active clinical development. Molecular imaging of DLL3 would enable non-invasive diagnostic assessment to inform the use of DLL3-targeting therapeutics or to assess disease treatment response. Methods: We conducted a first-in-human immuno-positron emission tomography (immunoPET) imaging study of [89Zr]Zr-DFO-SC16.56, composed of the anti-DLL3 antibody SC16.56 conjugated to desferrioxamine (DFO) and the positron-emitting radionuclide zirconium-89, in 18 patients with neuroendocrine cancers. An initial cohort of three patients received 1-2 mCi of [89Zr]Zr-DFO-SC16.56 at a total mass dose of 2·5 mg and underwent serial PET and computed tomography (CT) imaging over the course of one week. Radiotracer clearance, tumor uptake, and radiation dosimetry were estimated. An expansion cohort of 15 additional patients were imaged using the initial activity and mass dose. Retrospectively collected tumor biopsies were assessed for DLL3 by immunohistochemistry (IHC) (n = 16). Findings: Imaging of the initial 3 SCLC patients demonstrated strong tumor-specific uptake of [89Zr]Zr-DFO-SC16.56, with similar tumor: background ratios at days 3, 4, and 7 post-injection. Serum clearance was bi-phasic with an estimated terminal clearance half-time of 119 h. The sites of highest background tracer uptake were blood pool and liver. The normal tissue receiving the highest radiation dose was liver; 1·8 mGy/MBq, and the effective dose was 0.49 mSv/MBq. Tumoral uptake varied both between and within patients, and across anatomic sites, with a wide range in SUVmax (from 3·3 to 66·7). Tumor uptake by [89Zr]Zr-DFO-SC16.56 was associated with protein expression in all cases. Two non-avid DLL3 NEPC cases by PET scanning demonstrated the lowest DLL3 expression by tumor immunohistochemistry. Only one patient had a grade 1 allergic reaction, while no grade ≥2 adverse events noted. Interpretation: DLL3 PET imaging of patients with neuroendocrine cancers is safe and feasible. These results demonstrate the potential utility of [89Zr]Zr-DFO-SC16.56 for non-invasive in vivo detection of DLL3-expressing malignancies. Funding: Supported by NIH R01CA213448 (JTP), R35 CA263816 (CMR), U24 CA213274 (CMR), R35 CA232130 (JSL), and a Prostate Cancer Foundation TACTICAL Award (JSL), Scannell foundation. The Radiochemistry and Molecular Imaging Probes Core Facility is supported by NIH P30 CA08748.

Sex differences in brain tumor glutamine metabolism reveal sex-specific vulnerabilities to treatment.

BACKGROUND: Brain cancer incidence and mortality rates are greater in males. Understanding the molecular mechanisms that underlie those sex differences could improve treatment strategies. Although sex differences in normal metabolism are well described, it is currently unknown whether they persist in cancerous tissue. METHODS: Using positron emission tomography (PET) imaging and mass spectrometry, we assessed sex differences in glioma metabolism in samples from affected individuals. We assessed the role of glutamine metabolism in male and female murine transformed astrocytes using isotope labeling, metabolic rescue experiments, and pharmacological and genetic perturbations to modulate pathway activity. FINDINGS: We found that male glioblastoma surgical specimens are enriched for amino acid metabolites, including glutamine. Fluoroglutamine PET imaging analyses showed that gliomas in affected male individuals exhibit significantly higher glutamine uptake. These sex differences were well modeled in murine transformed astrocytes, in which male cells imported and metabolized more glutamine and were more sensitive to glutaminase 1 (GLS1) inhibition. The sensitivity to GLS1 inhibition in males was driven by their dependence on glutamine-derived glutamate for α-ketoglutarate synthesis and tricarboxylic acid (TCA) cycle replenishment. Females were resistant to GLS1 inhibition through greater pyruvate carboxylase (PC)-mediated TCA cycle replenishment, and knockdown of PC sensitized females to GLS1 inhibition. CONCLUSION: Our results show that clinically important sex differences exist in targetable elements of metabolism. Recognition of sex-biased metabolism may improve treatments through further laboratory and clinical research. FUNDING: This work was supported by NIH grants, Joshua's Great Things, the Siteman Investment Program, and the Barnard Research Fund.

Treatment Response and Clinical Outcomes of Well-Differentiated High-Grade Neuroendocrine Tumors to Lutetium-177-DOTATATE.

INTRODUCTION: Lutetium-177 (177Lu)-DOTATATE received FDA approval in 2018 to treat somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (NETs). Little data are available on response and outcomes for well-differentiated (WD) high-grade (HG) NETs treated with 177Lu-DOTATATE. MATERIALS AND METHODS: Patients with WD HG NETs treated with 177Lu-DOTATATE at MSK from 2018 to 2020 were identified. Demographics, response (RECIST 1.1), and progression-free survival (PFS) were determined. Next-generation sequencing (NGS) was performed in the archival tumor. RESULTS: Nineteen patients, all with progressive, heavily treated disease, were identified. Sites of tumor origin were: pancreas (74%), small bowel (11%), rectum (11%), and lung (5%); median Ki-67 was 32% (range 22-56). Thirteen patients (68%) completed all four 177Lu-DOTATATE cycles. Best response (N = 18 evaluable) was: 5/18 (28%) partial response, 8/18 (44%) stable disease, and 5/18 (28%) disease progression. Median PFS was 13.1 months (95% CI: 8.7-20.9). Most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; G3/4, 1 patient, 5%), anemia (7 patients, 37%; G3/4, 2 patients, 11%), leukopenia (6 patients, 32%; G3/4, 0 patients), and liver function test elevation (4 patients, 21%; G3/4, 0 patients). NGS results were available from 13/19 tumors (68%). The most observed alterations were in MEN1 (6/13, 46%) and DAXX (4/13, 31%). No RB1 alterations identified. CONCLUSION: We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with 177Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations.

Optimizing 90Y Particle Density Improves Outcomes After Radioembolization.

PURPOSE: To determine how particle density affects dose distribution and outcomes after lobar radioembolization. METHODS: Matched pairs of patients, treated with glass versus resin microspheres, were selected by propensity score matching (114 patients), in this single-institution retrospective study. For each patient, tumor and liver particle density (particles/cm3) and dose (Gy) were determined. Tumor-to-normal ratio was measured on both 99mTc-MAA SPECT/CT and post-90Y bremsstrahlung SPECT/CT. Microdosimetry simulations were used to calculate first percentile dose, which is the dose in the cold spots between microspheres. Local progression-free survival (LPFS) and overall survival were analyzed. RESULTS: As more particles were delivered, doses on 90Y SPECT/CT became more uniform throughout the treatment volume: tumor and liver doses became more similar (p = 0.04), and microscopic cold spots between particles disappeared. For hypervascular tumors (tumor-to-normal ratio ≥ 2.6 on MAA scan), delivering fewer particles (< 6000 particles/cm3 treatment volume) was associated with better LPFS (p = 0.03). For less vascular tumors (tumor-to-normal ratio < 2.6), delivering more particles (≥ 6000 particles/cm3) was associated with better LPFS (p = 0.02). In matched pairs of patients, using the optimal particle density resulted in improved overall survival (11.5 vs. 6.8 months, p = 0.047), compared to using suboptimal particle density. Microdosimetry resulted in better predictions of LPFS (p = 0.03), and overall survival (p = 0.02), compared to conventional dosimetry. CONCLUSION: The number of particles delivered can be chosen to maximize the tumor dose and minimize the liver dose, based on tumor vascularity. Optimizing the particle density resulted in improved LPFS and overall survival.

Chemical tools for epichaperome-mediated interactome dysfunctions of the central nervous system.

Diseases are a manifestation of how thousands of proteins interact. In several diseases, such as cancer and Alzheimer's disease, proteome-wide disturbances in protein-protein interactions are caused by alterations to chaperome scaffolds termed epichaperomes. Epichaperome-directed chemical probes may be useful for detecting and reversing defective chaperomes. Here we provide structural, biochemical, and functional insights into the discovery of epichaperome probes, with a focus on their use in central nervous system diseases. We demonstrate on-target activity and kinetic selectivity of a radiolabeled epichaperome probe in both cells and mice, together with a proof-of-principle in human patients in an exploratory single group assignment diagnostic study (ClinicalTrials.gov Identifier: NCT03371420). The clinical study is designed to determine the pharmacokinetic parameters and the incidence of adverse events in patients receiving a single microdose of the radiolabeled probe administered by intravenous injection. In sum, we introduce a discovery platform for brain-directed chemical probes that specifically modulate epichaperomes and provide proof-of-principle applications in their use in the detection, quantification, and modulation of the target in complex biological systems.

A Phase I Dose-Escalation and Expansion Study of Telaglenastat in Patients with Advanced or Metastatic Solid Tumors.

PURPOSE: Glutamine is a critical fuel for solid tumors. Interference with glutamine metabolism is deleterious to neoplasia in preclinical models. A phase I study of the oral, first-in-class, glutaminase (GLS) inhibitor telaglenastat was conducted in treatment-refractory solid tumor patients to define recommended phase II dose (RP2D) and evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity. PATIENTS AND METHODS: Dose escalation by 3 + 3 design was followed by exploratory tumor-/biomarker-specific cohorts. RESULTS: Among 120 patients, fatigue (23%) and nausea (19%) were the most common toxicity. Maximum tolerated dose was not reached. Correlative analysis indicated >90% GLS inhibition in platelets at plasma exposures >300 nmol/L, >75% tumoral GLS inhibition, and significant increase in circulating glutamine. RP2D was defined at 800 mg twice-daily. Disease control rate (DCR) was 43% across expansion cohorts (overall response rate 5%, DCR 50% in renal cell carcinoma). CONCLUSIONS: Telaglenastat is safe, with a favorable PK/PD profile and signal of antitumor activity, supporting further clinical development.

Phase 1 Trial of MLN0128 (Sapanisertib) and CB-839 HCl (Telaglenastat) in Patients With Advanced NSCLC (NCI 10327): Rationale and Study Design.

INTRODUCTION: There are currently no approved targeted therapies for lung squamous-cell carcinoma (LSCC) and KRAS-mutant lung adenocarcinoma (LUAD). About 30% of LSCC and 25% of KRAS-mutant LUAD exhibit hyperactive NRF2 pathway activation through mutations in NFE2L2 (the gene encoding NRF2) or its negative regulator, KEAP1. Preclinical data demonstrate that these tumors are uniquely sensitive to dual inhibition of glycolysis and glutaminolysis via mammalian target of rapamycin (mTOR) and glutaminase inhibitors. This phase 1 study was designed to assess safety and preliminary activity of the mTOR inhibitor MLN0128 (sapanisertib) in combination with the glutaminase inhibitor CB-839 HCl. METHODS: Phase 1 dose finding will use the queue-based variation of the 3 + 3 dose escalation scheme with the primary endpoint of identifying the recommended expansion dose. To confirm the acceptable tolerability of the recommended expansion dose, patients will subsequently enroll onto 1 of 4 expansion cohorts (n = 14 per cohort): (1) LSCC harboring NFE2L2 or (2) KEAP1 mutations, or (3) LUAD harboring KRAS/(KEAP1 or NFE2L2) coalterations, or (4) LSCC wild type for NFE2L2 and KEAP1. The primary endpoint of the dose expansion is to determine the preliminary efficacy of MLN0128/CB-839 combination therapy. CONCLUSION: This phase 1 study will determine the recommended expansion dose and preliminary efficacy of MLN0128 and CB-839 in advanced non-small-cell lung cancer with a focus on subsets of LSCC and KRAS-mutant LUAD harboring NFE2L2 or KEAP1 mutations.

Measuring Tumor Epichaperome Expression Using [124I] PU-H71 Positron Emission Tomography as a Biomarker of Response for PU-H71 Plus Nab-Paclitaxel in HER2-Negative Metastatic Breast Cancer.

PURPOSE: Epichaperome network maintenance is vital to survival of tumors that express it. PU-H71 is an epichaperome inhibitor that binds to the ATP-binding site of HSP90 and has demonstrated antitumor activity in breast cancer xenograft models and clinical safety in patients. PU-positron emission tomography (PET) is a theragnostic imaging tool that allows visualization of the epichaperome target. In this phase Ib trial, we present safety and tolerability for PU-H71 plus nab-paclitaxel in HER2-negative patients with metastatic breast cancer (MBC) and the utility of PU-PET as a noninvasive predictive biomarker. METHODS: We performed a 3 + 3 dose-escalation study with escalating PU-H71 doses and standard nab-paclitaxel. The primary objective was to establish safety and determine maximum tolerated dose (MTD)/recommended phase 2 dose. Secondary objectives were to assess pharmacokinetics and clinical efficacy. Patients could enroll in a companion PU-PET protocol to measure epichaperome expression before treatment initiation to allow exploratory correlation with treatment benefit. RESULTS: Of the 12 patients enrolled, dose-limiting toxicity occurred in one patient (G3 neutropenic fever) at dose level 1; MTD of PU-H71 was 300 mg/m2 plus nab-paclitaxel 260 mg/m2 administered every 3 weeks. Common toxicities included diarrhea, fatigue, peripheral neuropathy, and nausea. PU-H71 systemic exposure was not altered by nab-paclitaxel administration. Two of 12 patients had partial response (overall response rate, 17%) and the clinical benefit rate was 42% (5 of 12). Time to progression was associated with baseline epichaperome positivity and PU-H71 peak standard uptake value (SUV), with more durable disease control observed with high epichaperome levels. CONCLUSION: The combination of PU-H71 and nab-paclitaxel was well tolerated, with evidence of clinical activity. More durable disease control without progression was observed in patients with high baseline epichaperome expression. A phase II trial of this combination with PU-PET as a companion diagnostic for patient selection is currently planned.

The Unique Pharmacometrics of Small Molecule Therapeutic Drug Tracer Imaging for Clinical Oncology.

Translational development of radiolabeled analogues or isotopologues of small molecule therapeutic drugs as clinical imaging biomarkers for optimizing patient outcomes in targeted cancer therapy aims to address an urgent and recurring clinical need in therapeutic cancer drug development: drug- and target-specific biomarker assays that can optimize patient selection, dosing strategy, and response assessment. Imaging the in vivo tumor pharmacokinetics and biomolecular pharmacodynamics of small molecule cancer drugs offers patient- and tumor-specific data which are not available from other pharmacometric modalities. This review article examines clinical research with a growing pharmacopoeia of investigational small molecule cancer drug tracers.

Value of [18F]-FDG positron emission tomography in patients with recurrent glioblastoma receiving bevacizumab.

BACKGROUND: Treatment of recurrent glioblastoma (GBM) with bevacizumab can induce MRI changes that confound the determination of progression. We sought to determine the value of [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) in GBM patients receiving bevacizumab at the time of suspected progression and, thereby, its utility as a potential prognostic adjunct in progressive disease. METHODS: This retrospective study included patients who underwent brain FDG PET within 4 weeks of receiving bevacizumab for recurrent GBM with suspected progression. Volumes-of-interest were placed over the reference lesion with measurement of maximum standardized uptake value (SUVmax), peak standardized uptake value (SUVpeak), metabolic tumor volume, total lesion glycolysis (TLG), and tumor-to-normal contralateral white matter ratios (TNR-WM). Tumors were additionally categorized as non-avid or avid based on qualitative FDG uptake. Associations between baseline variables and overall survival (OS) were examined using univariable and multivariable Cox proportional hazards regression, with P < .05 considered significant. RESULTS: Thirty-one patients were analyzed. Qualitative FDG uptake was significantly associated with OS (P = .03), with a median OS of 9.0 months in non-avid patients versus 4.5 months in avid patients. SUVmax, SUVpeak, TNR-WM, and TLG were significantly associated with OS (P < .001, TLG: P = .009). FDG avidity and SUVmax remained significantly associated with OS (P = .046 and .048, respectively) in the multivariable analysis including age, KPS, and MGMT status. Dichotomizing patients using an SUVmax cutoff of 15.3 was associated with OS (adjusted P = .048). CONCLUSION: FDG PET is a promising imaging tool to further stratify prognosis in recurrent GBM patients on antiangiogenic therapy.

First-in-Human Trial of Epichaperome-Targeted PET in Patients with Cancer.

PURPOSE: 124I-PU-H71 is an investigational first-in-class radiologic agent specific for imaging tumor epichaperome formations. The intracellular epichaperome forms under cellular stress and is a clinically validated oncotherapeutic target. We conducted a first-in-human study of microdose 124I-PU-H71 for PET to study in vivo biodistribution, pharmacokinetics, metabolism, and safety; and the feasibility of epichaperome-targeted tumor imaging. EXPERIMENTAL DESIGN: Adult patients with cancer (n = 30) received 124I-PU-H71 tracer (201±12 MBq, <25 µg) intravenous bolus followed by PET/CT scans and blood radioassays. RESULTS: 124I-PU-H71 PET detected tumors of different cancer types (breast, lymphoma, neuroblastoma, genitourinary, gynecologic, sarcoma, and pancreas). 124I-PU-H71 was retained by tumors for several days while it cleared rapidly from bones, healthy soft tissues, and blood. Radiation dosimetry is favorable and patients suffered no adverse effects. CONCLUSIONS: Our first-in-human results demonstrate the safety and feasibility of noninvasive in vivo detection of tumor epichaperomes using 124I-PU-H71 PET, supporting clinical development of PU-H71 and other epichaperome-targeted therapeutics.

Safety and Feasibility of PARP1/2 Imaging with 18F-PARPi in Patients with Head and Neck Cancer.

PURPOSE: We performed a first-in-human clinical trial. The aim of this study was to determine safety and feasibility of PET imaging with 18F-PARPi in patients with head and neck cancer. PATIENTS AND METHODS: Eleven patients with newly diagnosed or recurrent oral and oropharyngeal cancer were injected with 18F-PARPi (331 ± 42 MBq), and dynamic PET/CT imaging was performed between 0 and 25 minutes postinjection. Static PET/CT scans were obtained at 30, 60, and 120 minutes postinjection. Blood samples for tracer concentration and metabolite analysis were collected. Blood pressure, ECG, oxygen levels, clinical chemistry, and complete blood count were obtained before and after tracer administration. RESULTS: 18F-PARPi was well-tolerated by all patients without any safety concerns. Of the 11 patients included in the analysis, 18F-PARPi had focal uptake in all primary lesions (n = 10, SUVmax = 2.8 ± 1.2) and all 18F-FDG-positive lymph nodes (n = 34). 18F-PARPi uptake was seen in 18F-FDG-negative lymph nodes of 3 patients (n = 6). Focal uptake of tracer in primary and metastatic lesions was corroborated by CT alone or in combination with 18F-FDG. The overall effective dose with 18F-PARPi PET was 3.9 mSv - 5.2 mSv, contrast was high [SUVmax(lesion)/SUVmax(trapezius muscle) = 4.5] and less variable than 18F-FDG when compared with the genioglossus muscle (1.3 vs. 6.0, P = 0.001). CONCLUSIONS: Imaging of head and neck cancer with 18F-PARPi is feasible and safe. 18F-PARPi detects primary and metastatic lesions, and retention in tumors is longer than in healthy tissues.

First-in-Humans Trial of Dasatinib-Derivative Tracer for Tumor Kinase-Targeted PET.

We developed a first-of-kind dasatinib-derivative imaging agent, 18F-SKI-249380 (18F-SKI), and validated its use for noninvasive in vivo tyrosine kinase-targeted tumor detection in preclinical models. In this study, we assessed the feasibility of using 18F-SKI for PET imaging in patients with malignancies. Methods: Five patients with a prior diagnosis of breast cancer, renal cell cancer, or leukemia underwent whole-body PET/CT imaging 90 min after injection of 18F-SKI (mean, 241.24 ± 116.36 MBq) as part of a prospective study. In addition, patients underwent either a 30-min dynamic scan of the upper abdomen including, at least partly, cardiac left ventricle, liver, spleen, and kidney (n = 2) or three 10-min whole-body PET/CT scans (n = 3) immediately after injection and blood-based radioactivity measurements to determine the time course of tracer distribution and facilitate radiation dose estimates. A subset of 3 patients had a delayed whole-body PET/CT scan at 180 min. Biodistribution, dosimetry, and tumor uptake were quantified. Absorbed doses were calculated using OLINDA/EXM 1.0. Results: No adverse events occurred after injection of 18F-SKI. In total, 27 tumor lesions were analyzed, with a median SUVpeak of 1.4 (range, 0.7-2.3) and tumor-to-blood ratios of 1.6 (range, 0.8-2.5) at 90 min after injection. The intratumoral drug concentrations calculated for 4 reference lesions ranged from 0.03 to 0.07 nM. In all reference lesions, constant tracer accumulation was observed between 30 and 90 min after injection. A blood radioassay indicated that radiotracer clearance from blood and plasma was initially rapid (blood half-time, 1.31 ± 0.81 min; plasma, 1.07 ± 0.66 min; n = 4), followed variably by either a prolonged terminal phase (blood half-time, 285 ± 148.49 min; plasma, 240 ± 84.85 min; n = 2) or a small rise to a plateau (n = 2). Like dasatinib, 18F-SKI underwent extensive metabolism after administration, as evidenced by metabolite analysis. Radioactivity was predominantly cleared via the hepatobiliary route. The highest absorbed dose estimates (mGy/MBq) in normal tissues were to the right colon (0.167 ± 0.04) and small intestine (0.153 ± 0.03). The effective dose was 0.0258 mSv/MBq (SD, 0.0034 mSv/MBq). Conclusion:18F-SKI demonstrated significant tumor uptake, distinct image contrast despite low injected doses, and rapid clearance from blood.

Circulating Tumor DNA Analysis to Assess Risk of Progression after Long-term Response to PD-(L)1 Blockade in NSCLC.

PURPOSE: Treatment with PD-(L)1 blockade can produce remarkably durable responses in patients with non-small cell lung cancer (NSCLC). However, a significant fraction of long-term responders ultimately progress and predictors of late progression are unknown. We hypothesized that circulating tumor DNA (ctDNA) analysis of long-term responders to PD-(L)1 blockade may differentiate those who will achieve ongoing benefit from those at risk of eventual progression. EXPERIMENTAL DESIGN: In patients with advanced NSCLC achieving long-term benefit from PD-(L)1 blockade (progression-free survival ≥ 12 months), plasma was collected at a surveillance timepoint late during/after treatment to interrogate ctDNA by Cancer Personalized Profiling by Deep Sequencing. Tumor tissue was available for 24 patients and was profiled by whole-exome sequencing (n = 18) or by targeted sequencing (n = 6). RESULTS: Thirty-one patients with NSCLC with long-term benefit to PD-(L)1 blockade were identified, and ctDNA was analyzed in surveillance blood samples collected at a median of 26.7 months after initiation of therapy. Nine patients also had baseline plasma samples available, and all had detectable ctDNA prior to therapy initiation. At the surveillance timepoint, 27 patients had undetectable ctDNA and 25 (93%) have remained progression-free; in contrast, all 4 patients with detectable ctDNA eventually progressed [Fisher P < 0.0001; positive predictive value = 1, 95% confidence interval (CI), 0.51-1; negative predictive value = 0.93 (95% CI, 0.80-0.99)]. CONCLUSIONS: ctDNA analysis can noninvasively identify minimal residual disease in patients with long-term responses to PD-(L)1 blockade and predict the risk of eventual progression. If validated, ctDNA surveillance may facilitate personalization of the duration of immune checkpoint blockade and enable early intervention in patients at high risk for progression.

The epichaperome is a mediator of toxic hippocampal stress and leads to protein connectivity-based dysfunction.

Optimal functioning of neuronal networks is critical to the complex cognitive processes of memory and executive function that deteriorate in Alzheimer's disease (AD). Here we use cellular and animal models as well as human biospecimens to show that AD-related stressors mediate global disturbances in dynamic intra- and inter-neuronal networks through pathologic rewiring of the chaperome system into epichaperomes. These structures provide the backbone upon which proteome-wide connectivity, and in turn, protein networks become disturbed and ultimately dysfunctional. We introduce the term protein connectivity-based dysfunction (PCBD) to define this mechanism. Among most sensitive to PCBD are pathways with key roles in synaptic plasticity. We show at cellular and target organ levels that network connectivity and functional imbalances revert to normal levels upon epichaperome inhibition. In conclusion, we provide proof-of-principle to propose AD is a PCBDopathy, a disease of proteome-wide connectivity defects mediated by maladaptive epichaperomes.

Preclinical and first-in-human-brain-cancer applications of [18F]poly (ADP-ribose) polymerase inhibitor PET/MR.

BACKGROUND: We report preclinical and first-in-human-brain-cancer data using a targeted poly (ADP-ribose) polymerase 1 (PARP1) binding PET tracer, [18F]PARPi, as a diagnostic tool to differentiate between brain cancers and treatment-related changes. METHODS: We applied a glioma model in p53-deficient nestin/tv-a mice, which were injected with [18F]PARPi and then sacrificed 1 h post-injection for brain examination. We also prospectively enrolled patients with brain cancers to undergo dynamic [18F]PARPi acquisition on a dedicated positron emission tomography/magnetic resonance (PET/MR) scanner. Lesion diagnosis was established by pathology when available or by Response Assessment in Neuro-Oncology (RANO) or RANO-BM response criteria. Resected tissue also underwent PARPi-FL staining and PARP1 immunohistochemistry. RESULTS: In a preclinical mouse model, we illustrated that [18F]PARPi crossed the blood-brain barrier and specifically bound to PARP1 overexpressed in cancer cell nuclei. In humans, we demonstrated high [18F]PARPi uptake on PET/MR in active brain cancers and low uptake in treatment-related changes independent of blood-brain barrier disruption. Immunohistochemistry results confirmed higher PARP1 expression in cancerous than in noncancerous tissue. Specificity was also corroborated by blocking fluorescent tracer uptake with an excess unlabeled PARP inhibitor in patient cancer biospecimen. CONCLUSIONS: Although larger studies are necessary to confirm and further explore this tracer, we describe the promising performance of [18F]PARPi as a diagnostic tool to evaluate patients with brain cancers and possible treatment-related changes.

Off-the-shelf EBV-specific T cell immunotherapy for rituximab-refractory EBV-associated lymphoma following transplantation.

BACKGROUNDAdoptive transfer of donor-derived EBV-specific cytotoxic T-lymphocytes (EBV-CTLs) can eradicate EBV-associated lymphomas (EBV-PTLD) after transplantation of hematopoietic cell (HCT) or solid organ (SOT) but is unavailable for most patients.METHODSWe developed a third-party, allogeneic, off-the-shelf bank of 330 GMP-grade EBV-CTL lines from specifically consented healthy HCT donors. We treated 46 recipients of HCT (n = 33) or SOT (n = 13) with established EBV-PTLD, who had failed rituximab therapy, with third-party EBV-CTLs. Treatment cycles consisted of 3 weekly infusions of EBV-CTLs and 3 weeks of observation.RESULTSEBV-CTLs did not induce significant toxicities. One patient developed grade I skin graft-versus-host disease. Complete remission (CR) or sustained partial remission (PR) was achieved in 68% of HCT recipients and 54% of SOT recipients. For patients who achieved CR/PR or stable disease after cycle 1, one year overall survival was 88.9% and 81.8%, respectively. In addition, 3 of 5 recipients with POD after a first cycle who received EBV-CTLs from a different donor achieved CR or durable PR (60%) and survived longer than 1 year. Maximal responses were achieved after a median of 2 cycles.CONCLUSIONThird-party EBV-CTLs of defined HLA restriction provide safe, immediately accessible treatment for EBV-PTLD. Secondary treatment with EBV-CTLs restricted by a different HLA allele (switch therapy) can also induce remissions if initial EBV-CTLs are ineffective. These results suggest a promising potential therapy for patients with rituximab-refractory EBV-associated lymphoma after transplantation.TRIAL REGISTRATIONPhase II protocols (NCT01498484 and NCT00002663) were approved by the Institutional Review Board at Memorial Sloan Kettering Cancer Center, the FDA, and the National Marrow Donor Program.FUNDINGThis work was supported by NIH grants CA23766 and R21CA162002, the Aubrey Fund, the Claire Tow Foundation, the Major Family Foundation, the Max Cure Foundation, the Richard "Rick" J. Eisemann Pediatric Research Fund, the Banbury Foundation, the Edith Robertson Foundation, and the Larry Smead Foundation. Atara Biotherapeutics licensed the bank of third-party EBV-CTLs from Memorial Sloan Kettering Cancer Center in June 2015.

Pharmacokinetic Assessment of 18F-(2S,4R)-4-Fluoroglutamine in Patients with Cancer.

18F-(2S,4R)-4-fluoroglutamine (18F-FGln) is an investigational PET radiotracer for imaging tumor glutamine flux and metabolism. The aim of this study was to investigate its pharmacokinetic properties in patients with cancer. Methods: Fifty lesions from 41 patients (21 men and 20 women, aged 54 ± 14 y) were analyzed. Thirty-minute dynamic PET scans were performed concurrently with a rapid intravenous bolus injection of 232 ± 82 MBq of 18F-FGln, followed by 2 static PET scans at 97 ± 14 and 190 ± 12 min after injection. Five patients also underwent a second 18F-FGln study 4-13 wk after initiation of therapy with glutaminase, dual TORC1/2, or programmed death-1 inhibitors. Blood samples were collected to determine plasma and metabolite fractions and to scale the image-derived input function. Regions of interest were manually drawn to calculate SUVs. Pharmacokinetic modeling with both reversible and irreversible 1- and 2-tissue-compartment models was performed to calculate the kinetic rate constants K1, k2, k3, and k4 The analysis was repeated with truncated 30-min dynamic datasets. Results: Intratumor 18F-FGln uptake patterns demonstrated substantial heterogeneity in different lesion types. In most lesions, the reversible 2-tissue-compartment model was chosen as the most appropriate according to the Akaike information criterion. K1, a surrogate biomarker for 18F-FGln intracellular transport, was the kinetic rate constant that was most correlated both with SUV at 30 min (Spearman ρ = 0.71) and with SUV at 190 min (ρ = 0.51). Only K1 was reproducible from truncated 30-min datasets (intraclass correlation coefficient, 0.96). k3, a surrogate biomarker for glutaminolysis rate, was relatively low in about 50% of lesions. Treatment with glutaminase inhibitor CB-839 substantially reduced the glutaminolysis rates as measured by k3Conclusion:18F-FGln dynamic PET is a sensitive tool for studying glutamine transport and metabolism in human malignancies. Analysis of dynamic data facilitates better understanding of 18F-FGln pharmacokinetics and may be necessary for response assessment to targeted therapies that impact intracellular glutamine pool size and tumor glutaminolysis rates.