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BACKGROUND: Addition of neoadjuvant immune checkpoint inhibition to standard-of-care interventions for locally advanced oral cancer could improve clinical outcome. METHODS: In this study, 16 evaluable patients with stage III/IV oral cancer were treated with one dose of 480 mg nivolumab 3 weeks prior to surgery. Primary objectives were safety, feasibility, and suitability of programmed death receptor ligand-1 positron emission tomography (PD-L1 PET) as a biomarker for response. Imaging included 18F-BMS-986192 (PD-L1) PET and 18F-fluorodeoxyglucose (FDG) PET before and after nivolumab treatment. Secondary objectives included clinical and pathological response, and immune profiling of peripheral blood mononuclear cells (PBMCs) for response prediction. Baseline tumor biopsies and postnivolumab resection specimens were evaluated by histopathology. RESULTS: Grade III or higher adverse events were not observed and treatment was not delayed in relation to nivolumab administration and other study procedures. Six patients (38%) had a pathological response, of whom three (19%) had a major (≥90%) pathological response (MPR). Tumor PD-L1 PET uptake (quantified using standard uptake value) was not statistically different in patients with or without MPR (median 5.3 vs 3.4). All major responders showed a significantly postnivolumab decreased signal on FDG PET. PBMC immune phenotyping showed higher levels of CD8+ T cell activation in MPR patients, evidenced by higher baseline expression levels of PD-1, TIGIT, IFNγ and lower levels of PD-L1. CONCLUSION: Together these data support that neoadjuvant treatment of advanced-stage oral cancers with nivolumab was safe and induced an MPR in a promising 19% of patients. Response was associated with decreased FDG PET uptake as well as activation status of peripheral T cell populations.
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Neoplasias de la Boca , Terapia Neoadyuvante , Humanos , Masculino , Femenino , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/diagnóstico por imagen , Neoplasias de la Boca/patología , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Anciano , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Imagen Molecular/métodos , Nivolumab/uso terapéutico , Nivolumab/farmacología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Tomografía de Emisión de Positrones/métodos , AdultoRESUMEN
INTRODUCTION: Immune checkpoint inhibitors (ICIs) can elicit anticancer immune responses, but predictive biomarkers are needed. We measured programmed death ligand 1 (PD-L1) expression in organs and lymph nodes using 18F-BMS-986192 positron emission tomography (PET)-imaging and looked for correlations with response and immune-related adverse events. METHODS: Four 18F-BMS-986192 PET studies in patients with melanoma, lung, pancreatic and oral cancer, receiving ICI treatment, were combined. Imaging data (organ standardized uptake value (SUV)mean, lymph node SUVmax) and clinical data (response to treatment and incidence of immune-related adverse events) were extracted. RESULTS: Baseline PD-L1 uptake in the spleen was on average higher in non-responding patients than in responders (spleen SUVmean 16.1±4.4 vs 12.5±3.4, p=0.02). This effect was strongest in lung cancer, and not observed in oral cancer. In the oral cancer cohort, benign tumor-draining lymph nodes (TDLNs) had higher PD-L1 uptake (SUVmax 3.3 IQR 2.5-3.9) compared with non-TDLNs (SUVmax 1.8, IQR 1.4-2.8 p=0.04). Furthermore, in the same cohort non-responders showed an increase in PD-L1 uptake in benign TDLNs on-treatment with ICIs (+15%), while for responders the PD-L1 uptake decreased (-11%). PD-L1 uptake did not predict immune-related adverse events, though elevated thyroid uptake on-treatment correlated with pre-existing thyroid disease or toxicity. CONCLUSION: PD-L1 PET uptake in the spleen is a potential negative predictor of response to ICIs. On-treatment with ICIs, PD-L1 uptake in benign TDLNs increases in non-responders, while it decreases in responders, potentially indicating a mechanism for resistance to ICIs in patients with oral cancer.
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Antígeno B7-H1 , Ganglios Linfáticos , Tomografía de Emisión de Positrones , Humanos , Antígeno B7-H1/metabolismo , Ganglios Linfáticos/metabolismo , Ganglios Linfáticos/patología , Ganglios Linfáticos/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Masculino , Femenino , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/diagnóstico por imagen , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Persona de Mediana Edad , AncianoRESUMEN
INTRODUCTION: 89Zr-immuno-PET (positron emission tomography with zirconium-89-labeled monoclonal antibodies ([89Zr]Zr-mAbs)) can be used to study the biodistribution of mAbs targeting the immune system. The measured uptake consists of target-specific and non-specific components, and it can be influenced by plasma availability of the tracer. To find evidence for target-specific uptake, i.e., target engagement, we studied five immune-checkpoint-targeting [89Zr]Zr-mAbs to (1) compare the uptake with previously reported baseline values for non-specific organ uptake (ns-baseline) and (2) look for saturation effects of increasing mass doses. METHOD: 89Zr-immuno-PET data from five [89Zr]Zr-mAbs, i.e., nivolumab and pembrolizumab (anti-PD-1), durvalumab (anti-PD-L1), BI 754,111 (anti-LAG-3), and ipilimumab (anti-CTLA-4), were analysed. For each mAb, 2-3 different mass doses were evaluated. PET scans and blood samples from at least two time points 24 h post injection were available. In 35 patients, brain, kidneys, liver, spleen, lungs, and bone marrow were delineated. Patlak analysis was used to account for differences in plasma activity concentration and to quantify irreversible uptake (Ki). To identify target engagement, Ki values were compared to ns-baseline Ki values previously reported, and the effect of increasing mass doses on Ki was investigated. RESULTS: All mAbs, except ipilimumab, showed Ki values in spleen above the ns-baseline for the lowest administered mass dose, in addition to decreasing Ki values with higher mass doses, both indicative of target engagement. For bone marrow, no ns-baseline was established previously, but a similar pattern was observed. For kidneys, most mAbs showed Ki values within the ns-baseline for both low and high mass doses. However, with high mass doses, some saturation effects were seen, suggestive of a lower ns-baseline value. Ki values were near zero in brain tissue for all mass doses of all mAbs. CONCLUSION: Using Patlak analysis and the established ns-baseline values, evidence for target engagement in (lymphoid) organs for several immune checkpoint inhibitors could be demonstrated. A decrease in the Ki values with increasing mass doses supports the applicability of Patlak analysis for the assessment of target engagement for PET ligands with irreversible uptake behavior.
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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.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias de Cabeza y Cuello , Neoplasias Pulmonares , Humanos , Radioisótopos , Carcinoma de Células Escamosas de Cabeza y Cuello , Tomografía de Emisión de Positrones/métodos , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Circonio , Línea Celular TumoralRESUMEN
Nanomedicines are used to improve the efficacy and safety of pharmacotherapeutic interventions. Unraveling the biological behavior of nanomedicines, including their biodistribution and target site accumulation, is essential to establish design criteria that contribute to superior performance. CriPec® technology is based on amphiphilic methoxy-poly(ethylene glycol)-b-poly[N-(2-hydroxypropyl) methacrylamide lactate] (mPEG-b-pHPMAmLacn) block copolymers, which are designed to upon self-assembly covalently entrap active pharmaceutical ingredients (API) in core-crosslinked polymeric micelles (CCPM). Key features of CCPM are a prolonged circulation time, high concentrations at pathological sites, and low levels of accumulation in the majority of healthy tissues. Proprietary hydrolysable linkers allow for tunable and sustained release of entrapped API, including hydrophobic and hydrophilic small molecules, as well as peptides and oligonucleotides. Preclinical imaging experiments provided valuable information on their tumor and tissue accumulation and distribution, as well as on uptake by cancer, healthy and immune cells. The frontrunner formulation CPC634, which refers to 65 nm-sized CCPM entrapping the chemotherapeutic drug docetaxel, showed excellent pharmacokinetic properties, safety, tumor accumulation and antitumor efficacy in multiple animal models. In the clinic, CPC634 also demonstrated favorable pharmacokinetics, good tolerability, signs of efficacy, and enhanced localization in tumor tissue as compared to conventional docetaxel. PET imaging of radiolabeled CPC634 showed quantifiable accumulation in â¼50 % of tumors and metastases in advanced-stage cancer patients, and demonstrated potential for use in a theranostic setting even when applied at a companion diagnostic dose. Altogether, the preclinical and clinical results obtained to date demonstrate that mPEG-b-pHPMAmLacn CCPM based on CriPec® technology are a potent, tunable, broadly applicable and well-tolerable platform for targeted drug delivery and improved anticancer therapy.
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Antineoplásicos , Neoplasias , Animales , Micelas , Docetaxel/farmacocinética , Distribución Tisular , Portadores de Fármacos/química , Polietilenglicoles/química , Polímeros/química , Neoplasias/tratamiento farmacológico , Antineoplásicos/uso terapéuticoRESUMEN
In this PD-L1 ImagiNg to prediCt durvalumab treatment response in SCCHN (PINCH) study, we performed 89Zr-DFO-durvalumab (anti-PD-L1 [programmed death ligand 1]) PET/CT in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) before monotherapy durvalumab treatment. The primary aims were to assess safety and feasibility of 89Zr-DFO-durvalumab PET imaging and predict disease control rate during durvalumab treatment. Secondary aims were to correlate 89Zr-DFO-durvalumab uptake to tumor PD-L1 expression, 18F-FDG uptake, and treatment response of individual lesions. Methods: In this prospective multicenter phase I-II study (NCT03829007), patients with incurable R/M SCCHN underwent baseline 18F-FDG PET and CT or MRI. Subsequently, PD-L1 PET imaging was performed 5 d after administration of 37 MBq of 89Zr-DFO-durvalumab. To optimize imaging conditions, dose finding was performed in the first 14 patients. For all patients (n = 33), durvalumab treatment (1,500 mg/4 wk, intravenously) was started within 1 wk after PD-L1 PET imaging and continued until disease progression or unacceptable toxicity (maximum, 24 mo). CT evaluation was assessed according to RECIST 1.1 every 8 wk. PD-L1 expression was determined by combined positive score on (archival) tumor tissue. 89Zr-DFO-durvalumab uptake was measured in 18F-FDG-positive lesions, primary and secondary lymphoid organs, and blood pool. Results: In total, 33 patients with locoregional recurrent (n = 12) or metastatic SCCHN (n = 21) were enrolled. 89Zr-DFO-durvalumab injection was safe. A dose of 10 mg of durvalumab resulted in highest tumor-to-blood ratios. After a median follow-up of 12.6 mo, overall response rate was 26%. The disease control rate at 16 wk was 48%, with a mean duration of 7.8 mo (range, 1.7-21.1). On a patient level, 89Zr-DFO-durvalumab SUVpeak or tumor-to-blood ratio could not predict treatment response (hazard ratio, 1.5 [95% CI, 0.5-3.9; P = 0.45] and 1.3 [95% CI, 0.5-3.3; P = 0.60], respectively). Also, on a lesion level, 89Zr-DFO-durvalumab SUVpeak showed no substantial correlation to treatment response (Spearman ρ, 0.45; P = 0.051). Lesional 89Zr-DFO-durvalumab uptake did not correlate to PD-L1 combined positive score but did correlate to 18F-FDG SUVpeak (Spearman ρ, 0.391; P = 0.005). Conclusion: PINCH is the first, to our knowledge, PD-L1 PET/CT study in patients with R/M SCCHN and has shown the feasibility and safety of 89Zr-DFO-durvalumab PET/CT in a multicenter trial. 89Zr-DFO-durvalumab uptake did not correlate to durvalumab treatment response.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Anticuerpos Monoclonales , Antígeno B7-H1/metabolismo , Fluorodesoxiglucosa F18 , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Humanos , Recurrencia Local de Neoplasia/diagnóstico por imagen , Recurrencia Local de Neoplasia/tratamiento farmacológico , Tomografía Computarizada por Tomografía de Emisión de Positrones , Estudios Prospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello/diagnóstico por imagen , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológicoRESUMEN
Several FDA/EMA-approved nanomedicines have demonstrated improved pharmacokinetics and toxicity profiles compared to their conventional chemotherapeutic counterparts. The next step to increase therapeutic efficacy depends on tumor accumulation, which can be highly heterogeneous. A clinical tool for patient stratification is urgently awaited. Therefore, a docetaxel-entrapping polymeric nanoparticle (89 Zr-CPC634) is radiolabeled, and positron emission tomography/computed tomography (PET/CT) imaging is performed in seven patients with solid tumors with two different doses of CPC634: an on-treatment (containing 60 mg m-2 docetaxel) and a diagnostic (1-2 mg docetaxel) dose (NCT03712423). Pharmacokinetic half-life for 89 Zr-CPC634 is mean 97.0 ± 14.4 h on-treatment, and 62.4 ± 12.9 h for the diagnostic dose (p = 0.003). At these doses accumulation is observed in 46% and 41% of tumor lesions with a median accumulation in positive lesions 96 h post-injection of 4.94 and 4.45%IA kg-1 (p = 0.91), respectively. In conclusion, PET/CT imaging with a diagnostic dose of 89 Zr-CPC634 accurately reflects on-treatment tumor accumulation and thus opens the possibility for patient stratification in cancer nanomedicine with polymeric nanoparticles.
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Nanopartículas , Neoplasias , Docetaxel/uso terapéutico , Humanos , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Polímeros/uso terapéutico , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Tomografía de Emisión de Positrones/métodos , CirconioRESUMEN
PURPOSE: Praluzatamab ravtansine (CX-2009) is a conditionally activated Probody drug conjugate (PDC) comprising an anti-CD166 mAb conjugated to DM4, with a protease-cleavable linker and a peptide mask that limits target engagement in normal tissue and circulation. The tumor microenvironment is enriched for proteases capable of cleaving the linker, thereby releasing the mask, allowing for localized binding of CX-2009 to CD166. CX-2009 was evaluated in a phase I/II clinical trial for patients with advanced solid tumors. PATIENTS AND METHODS: Eligible patients had metastatic cancer receiving ≥2 prior treatments. CX-2009 was administered at escalating doses every 3 weeks (0.25-10 mg/kg) or every 2 weeks (4-6 mg/kg). Primary objective was to determine the safety profile and recommended phase II dose (RP2D). RESULTS: Of 99 patients enrolled, the most prevalent subtype was breast cancer (n = 45). Median number of prior therapies was 5 (range, 1-19). Dose-limiting toxicities were observed at 8 mg/kg every 3 weeks and 6 mg/kg every 2 weeks. On the basis of tolerability, the RP2D was 7 mg/kg every 3 weeks. Tumor regressions were observed at doses ≥4 mg/kg. In the hormone receptor-positive/HER2-nonamplified breast cancer subset (n = 22), 2 patients (9%) had confirmed partial responses, and 10 patients (45%) had stable disease. Imaging with zirconium-labeled CX-2009 confirmed uptake in tumor lesions and shielding of major organs. Activated, unmasked CX-2009 was measurable in 18 of 22 posttreatment biopsies. CONCLUSIONS: CD166 is a novel, ubiquitously expressed target. CX-2009 is the first conditionally activated antibody-drug conjugate to CD166 to demonstrate both translational and clinical activity in a variety of tumor types.
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Antineoplásicos , Neoplasias de la Mama , Inmunoconjugados , Maitansina , Neoplasias , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Humanos , Inmunoconjugados/efectos adversos , Maitansina/uso terapéutico , Neoplasias/patología , Microambiente TumoralRESUMEN
Immunoglobulin light chain (AL) amyloidosis is characterized by the deposition of amyloid fibers derived from pathologic immunoglobulin light chains. Although systemic plasma cell neoplasms are the most common cause of AL amyloidosis, a subset of cases is caused by B-cell lymphoproliferative disorders such as lymphoplasmacytic lymphoma or extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. Recently, SOX11-negative IGH hypermutated mantle cell lymphoma (MCL) is recognized to show frequent plasmacytic differentiation and indolent clinical course. Here, we report 3 cases of peritumoral AL amyloidosis associated with SOX11-negative MCL. All 3 cases showed cyclin D1 expression by immunohistochemistry and CCND1 translocation as detected by fluorescence in situ hybridization analysis. Peritumoral AL amyloidosis was observed at the biopsy sites in the gastrointestinal tract, a supraclavicular lymph node, and a cervical lymph node, and all presented with marked plasmacytic differentiation of lymphoma cells. None of the cases showed evidence of bone marrow involvement by morphology and immunophenotyping. None of the patients had distant organ involvement with systemic amyloidosis. All 3 patients had an indolent clinical course and are alive with disease at the time of the last follow-up (range: 48 to 74 mo). Our findings show that MCL with plasmacytic differentiation can cause amyloid deposition and CCND1 abnormalities should be performed in all cases of extramedullary AL amyloidosis. Recognition of indolent MCL as a cause of peritumoral AL amyloidosis may have important clinical management implications.
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Diferenciación Celular , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/patología , Linfoma de Células del Manto/patología , Células Plasmáticas/patología , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Ciclina D1/genética , Femenino , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/tratamiento farmacológico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/genética , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/inmunología , Inmunohistoquímica , Hibridación Fluorescente in Situ , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/genética , Linfoma de Células del Manto/inmunología , Persona de Mediana Edad , Células Plasmáticas/efectos de los fármacos , Células Plasmáticas/inmunología , Estudios Retrospectivos , Translocación Genética , Resultado del TratamientoRESUMEN
We report the development and validation of a 12 parameter immunofluorescence flow cytometry method for the sensitive determination of cell concentrations, their expression of PD-1, and PD-1 receptor occupancy. Cell subsets include CD4+ and CD8+ -T-cells, B-cells, natural killer cells, classical-, intermediate- and non-classical monocytes, and myeloid- and plasmacytoid dendritic cells. Cells were isolated from peripheral blood by density gradient centrifugation. The validation parameters included specificity, linearity, limit of quantification, precision, biological within- and between subject variations. The lower limit of quantification was 5.0% of PD-1+ cells. Samples were stable for at least 153 days of storage at -80°C. The clinical applicability of the method was demonstrated in 11 advanced cancer patients by the successful determination of immune cell concentrations, relative number of PD-1+ immune cells, and number of PD-1 molecules per immune cell. Shortly after infusion of nivolumab, receptor occupancy on CD8+ -T-cells was 98%. Similar values were found predose cycle 2, suggesting receptor occupancy remained high throughout the entire cycle. © 2019 International Society for Advancement of Cytometry.