Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 40
Filter
1.
Sci Data ; 11(1): 448, 2024 May 03.
Article in English | MEDLINE | ID: mdl-38702329

ABSTRACT

Time-critical transcriptional events in the immune microenvironment are important for response to immune checkpoint blockade (ICB), yet these events are difficult to characterise and remain incompletely understood. Here, we present whole tumor RNA sequencing data in the context of treatment with ICB in murine models of AB1 mesothelioma and Renca renal cell cancer. We sequenced 144 bulk RNAseq samples from these two cancer types across 4 time points prior and after treatment with ICB. We also performed single-cell sequencing on 12 samples of AB1 and Renca tumors an hour before ICB administration. Our samples were equally distributed between responders and non-responders to treatment. Additionally, we sequenced AB1-HA mesothelioma tumors treated with two sample dissociation protocols to assess the impact of these protocols on the quality transcriptional information in our samples. These datasets provide time-course information to transcriptionally characterize the ICB response and provide detailed information at the single-cell level of the early tumor microenvironment prior to ICB therapy.


Subject(s)
Carcinoma, Renal Cell , Immune Checkpoint Inhibitors , Kidney Neoplasms , Mesothelioma , Tumor Microenvironment , Animals , Mice , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/genetics , Immune Checkpoint Inhibitors/therapeutic use , Kidney Neoplasms/drug therapy , Kidney Neoplasms/genetics , Mesothelioma/drug therapy , Mesothelioma/genetics , RNA-Seq , Sequence Analysis, RNA , Single-Cell Analysis
2.
Oncoimmunology ; 13(1): 2345859, 2024.
Article in English | MEDLINE | ID: mdl-38686178

ABSTRACT

Immune checkpoint therapy (ICT) causes durable tumour responses in a subgroup of patients, but it is not well known how T cell receptor beta (TCRß) repertoire dynamics contribute to the therapeutic response. Using murine models that exclude variation in host genetics, environmental factors and tumour mutation burden, limiting variation between animals to naturally diverse TCRß repertoires, we applied TCRseq, single cell RNAseq and flow cytometry to study TCRß repertoire dynamics in ICT responders and non-responders. Increased oligoclonal expansion of TCRß clonotypes was observed in responding tumours. Machine learning identified TCRß CDR3 signatures unique to each tumour model, and signatures associated with ICT response at various timepoints before or during ICT. Clonally expanded CD8+ T cells in responding tumours post ICT displayed effector T cell gene signatures and phenotype. An early burst of clonal expansion during ICT is associated with response, and we report unique dynamics in TCRß signatures associated with ICT response.


Subject(s)
Immune Checkpoint Inhibitors , Lymphocytes, Tumor-Infiltrating , Receptors, Antigen, T-Cell, alpha-beta , Animals , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Receptors, Antigen, T-Cell, alpha-beta/genetics , Receptors, Antigen, T-Cell, alpha-beta/metabolism , Mice , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/drug effects , Lymphocytes, Tumor-Infiltrating/metabolism , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/metabolism , Humans , Mice, Inbred C57BL , Female
3.
Nat Commun ; 13(1): 4895, 2022 08 19.
Article in English | MEDLINE | ID: mdl-35986006

ABSTRACT

The biological determinants of the response to immune checkpoint blockade (ICB) in cancer remain incompletely understood. Little is known about dynamic biological events that underpin therapeutic efficacy due to the inability to frequently sample tumours in patients. Here, we map the transcriptional profiles of 144 responding and non-responding tumours within two mouse models at four time points during ICB. We find that responding tumours display on/fast-off kinetics of type-I-interferon (IFN) signaling. Phenocopying of this kinetics using time-dependent sequential dosing of recombinant IFNs and neutralizing antibodies markedly improves ICB efficacy, but only when IFNß is targeted, not IFNα. We identify Ly6C+/CD11b+ inflammatory monocytes as the primary source of IFNß and find that active type-I-IFN signaling in tumour-infiltrating inflammatory monocytes is associated with T cell expansion in patients treated with ICB. Together, our results suggest that on/fast-off modulation of IFNß signaling is critical to the therapeutic response to ICB, which can be exploited to drive clinical outcomes towards response.


Subject(s)
Interferon Type I , Neoplasms , Animals , Interferon-alpha , Interferon-beta/genetics , Interferon-beta/therapeutic use , Mice , Neoplasms/drug therapy , Neoplasms/genetics , Signal Transduction
4.
Front Oncol ; 12: 849793, 2022.
Article in English | MEDLINE | ID: mdl-35402250

ABSTRACT

With immune checkpoint therapy (ICT) having reshaped the treatment of many cancers, the next frontier is to identify and develop novel combination therapies to improve efficacy. Previously, we and others identified beneficial immunological effects of the vitamin A derivative tretinoin on anti-tumour immunity. Although it is known that tretinoin preferentially depletes myeloid derived suppressor cells in blood, little is known about the effects of tretinoin on the tumour microenvironment, hampering the rational design of clinical trials using tretinoin in combination with ICT. Here, we aimed to identify how tretinoin changed the tumour microenvironment in mouse tumour models, using flow cytometry and RNAseq, and we sought to use that information to establish optimal dosing and scheduling of tretinoin in combination with several ICT antibodies in multiple cancer models. We found that tretinoin rapidly induced an interferon dominated inflammatory tumour microenvironment, characterised by increased CD8+ T cell infiltration. This phenotype completely overlapped with the phenotype that was induced by ICT itself, and we confirmed that the combination further amplified this inflammatory milieu. The addition of tretinoin significantly improved the efficacy of anti-CTLA4/anti-PD-L1 combination therapy, and staggered scheduling was more efficacious than concomitant scheduling, in a dose-dependent manner. The positive effects of tretinoin could be extended to ICT antibodies targeting OX40, GITR and CTLA4 monotherapy in multiple cancer models. These data show that tretinoin induces an interferon driven, CD8+ T cell tumour microenvironment that is responsive to ICT.

5.
Sci Rep ; 11(1): 15312, 2021 07 28.
Article in English | MEDLINE | ID: mdl-34321489

ABSTRACT

Advances in cancer immunology have increased the use of immune checkpoint inhibitors in clinical practice, however not all patients respond, and treatment can have severe side-effects. Blood-based immunological biomarkers are an attractive method for predicting which patients will respond to therapy, however, reliable biomarkers for immune checkpoint blockade are lacking. This study aimed to identify patients before or early in treatment who would best respond to PD-1 inhibitors. We hypothesised that higher baseline PD-L1 and/or PD-1 on peripheral blood T cells could predict radiological response to PD-1 inhibitors. This pilot prospective cohort study assessed 26 patients with melanoma or non-small cell lung cancer, treated with pembrolizumab, nivolumab, or nivolumab/ipilimumab combined. Response was assessed by RECIST 1.1. Peripheral blood lymphocytes collected at baseline, after one cycle, 10 weeks and at discontinuation of therapy were analysed by flow cytometry. Patients with a higher proportion of PD-L1+ T cells at baseline had improved objective response to PD-1 inhibitor therapy, and patients with a lower proportion of regulatory T cells at baseline experienced more immune-related adverse events. These findings may prove useful to assist in clinical decision making. Further studies with larger cohorts are required to validate these findings.


Subject(s)
B7-H1 Antigen/biosynthesis , Carcinoma, Non-Small-Cell Lung/metabolism , Gene Expression Regulation, Neoplastic/drug effects , Immune Checkpoint Inhibitors/pharmacology , Lung Neoplasms/metabolism , Melanoma/metabolism , Molecular Targeted Therapy , Neoplasm Proteins/biosynthesis , T-Lymphocytes/drug effects , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Female , Humans , Immune Checkpoint Inhibitors/adverse effects , Immune Checkpoint Inhibitors/therapeutic use , Ipilimumab/administration & dosage , Ipilimumab/adverse effects , Ipilimumab/pharmacology , Kaplan-Meier Estimate , Lung Neoplasms/drug therapy , Male , Melanoma/drug therapy , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/genetics , Nivolumab/administration & dosage , Nivolumab/adverse effects , Nivolumab/pharmacology , Nivolumab/therapeutic use , Pilot Projects , Progression-Free Survival , Prospective Studies , T-Lymphocytes, Regulatory/drug effects
6.
Expert Rev Anticancer Ther ; 21(5): 465-474, 2021 05.
Article in English | MEDLINE | ID: mdl-33509005

ABSTRACT

Background: Single-agent cyclophosphamide can deplete regulatory T-cells (Treg). We aimed to determine optimal dosing and scheduling of oral cyclophosphamide, alongside pemetrexed-based chemotherapy, to deplete Treg in mesothelioma or non-small-cell lung cancer patients.Methods: 31 Patients received pemetrexed ± cisplatin or carboplatin on day 1 of a 21-day cycle (maximum 6 cycles). From cycle two, patients received cyclophosphamide, 50 mg/day, with intrapatient escalation to maximum 100/150 mg/day alternately. Immunological changes were examined by flow cytometry. Primary endpoint was Treg proportion of CD4+ T-cells, with doses tailored to target Treg nadir <4%.Results: Reduction in Treg proportion was observed on day 8 of all cycles, and was not augmented by cyclophosphamide. Few patients achieved the <4% Treg target. Treg proliferation reached nadir one week after chemotherapy, and peaked on day 1 of the subsequent cycle. Efficacy parameters were similar to chemotherapy alone. Seventeen percent of patients ceased cyclophosphamide due to toxicity.Conclusions: Specific Treg depletion to the degree seen with single-agent cyclophosphamide was not observed during pemetrexed-based chemotherapy. This study highlights the poor evidence basis for use of cyclophosphamide as an immunotherapeutic in combination with chemotherapy, and the importance of detailed flow cytometry studies.Trial registration: Clinical trial registration: www.anzctr.org.au identifier is ACTRN12609000260224.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Antineoplastic Combined Chemotherapy Protocols , Carcinoma, Non-Small-Cell Lung/drug therapy , Cisplatin , Cyclophosphamide/administration & dosage , Cyclophosphamide/toxicity , Humans , Lung Neoplasms/drug therapy , Pemetrexed , Platinum/therapeutic use , T-Lymphocytes, Regulatory
7.
Cancer Epidemiol Biomarkers Prev ; 29(11): 2203-2210, 2020 11.
Article in English | MEDLINE | ID: mdl-32856602

ABSTRACT

BACKGROUND: Scalp and neck (SN) melanoma confers a worse prognosis than melanoma of other sites but little is known about its determinants. We aimed to identify associations between SN melanoma and known risk genes, phenotypic traits, and sun exposure patterns. METHODS: Participants were cases from the Western Australian Melanoma Health Study (n = 1,200) and the Genes, Environment, and Melanoma Study (n = 3,280). Associations between risk factors and SN melanoma, compared with truncal and arm/leg melanoma, were investigated using binomial logistic regression. Facial melanoma was also compared with the trunk and extremities, to evaluate whether associations were subregion specific, or reflective of the whole head/neck region. RESULTS: Compared with other sites, increased odds of SN and facial melanoma were observed in older individuals [SN: OR = 1.28, 95% confidence interval (CI) = 0.92-1.80, P trend = 0.016; Face: OR = 4.57, 95% CI = 3.34-6.35, P trend < 0.001] and those carrying IRF4-rs12203592*T (SN: OR = 1.35, 95% CI = 1.12-1.63, P trend = 0.002; Face: OR = 1.29, 95% CI = 1.10-1.50, P trend = 0.001). Decreased odds were observed for females (SN: OR = 0.49, 95% CI = 0.37-0.64, P < 0.001; Face: OR = 0.66, 95% CI = 0.53-0.82, P < 0.001) and the presence of nevi (SN: OR = 0.66, 95% CI = 0.49-0.89, P = 0.006; Face: OR = 0.65, 95% CI = 0.52-0.83, P < 0.001). CONCLUSIONS: Differences observed between SN melanoma and other sites were also observed for facial melanoma. Factors previously associated with the broader head and neck region, notably older age, may be driven by the facial subregion. A novel finding was the association of IRF4-rs12203592 with both SN and facial melanoma. IMPACT: Understanding the epidemiology of site-specific melanoma will enable tailored strategies for risk factor reduction and site-specific screening campaigns.


Subject(s)
Melanoma/complications , Neck/pathology , Scalp/pathology , Skin Neoplasms/complications , Aged , Female , Humans , Male , Melanoma/physiopathology , Middle Aged , Risk Factors , Skin Neoplasms/physiopathology
8.
Thyroid ; 30(9): 1254-1262, 2020 09.
Article in English | MEDLINE | ID: mdl-32538690

ABSTRACT

Introduction: Multikinase inhibitors have clinical activity in radioactive iodine refractory (RAIR) differentiated thyroid cancers (DTCs) but are not curative; optimal management and salvage therapies remain unclear. This study assessed clinical effects of pazopanib therapy in RAIR-DTC patients with progressive disease, examining in parallel biomarker that might forecast/precede therapeutic response. Methods: Assessment of responses and toxicities and of any association between thyroglobulin (Tg) changes cycle 1 and RECIST (response evaluation criteria in solid tumors) response to pazopanib therapy were prospectively undertaken in Tg antibody negative RAIR-DTC patients. RECIST progressive metastatic disease <6 months preceding enrollment was required. With a sample size of 68 (assuming 23 attaining partial response [PR]), there would be 90% chance of detecting a difference of >30% when the proportion of patients attaining PR whose Tg values decrease by >50% is >50% cycle 1 (one-sided α = 0.10, two sample test of proportions). Mean corpuscular volume (MCV) change or mutational status or pretreatment were also explored as early correlates of eventual RECIST response. Results: From 2009 to 2011, 60 individuals were treated and evaluated; (one additional patient withdrew; another was found ineligible before therapy initiation); 91.7% had previous systemic therapy beyond RAI. Adverse events included one death (thromboembolic) deemed possibly pazopanib associated. Twenty-two confirmed RECIST PRs resulted (36.7%, confidence interval; CI [24.6-50.1]); mean administered 4-week cycles was 10. Among 44 fully accessible patients, the Tg nadir was greater among the 20 attaining PR (median: -86.8%; interquartile range [IQR]: -90.7% to -70.9%) compared with the 28 who did not (median: -69.0%; IQR: -78.1% to -27.7%, Wilcoxon rank-sum test: p = 0.002). However, the difference in the proportion of PRs among those whose Tg fell ≥50% after cycle 1 versus those that did not were not significantly correlated (-23.5% [CI: -55.3 to 8.3]; Fisher's exact test p-value = 0.27). RECIST response was also not correlated with/predicted by early MCV change, receipt of prior therapy, or tumor mutational status. Conclusions: This trial prospectively confirmed pazopanib to have clinical activity and manageable toxicities in patients with progressive RAIR-DTC. Response to pazopanib, however, was not robustly forecast by early associated changes in Tg or MCV, by prior therapy, or by tumor mutational status. ClinicalTrials.gov NCT00625846.


Subject(s)
Indazoles/therapeutic use , Pyrimidines/therapeutic use , Sulfonamides/therapeutic use , Thyroglobulin/immunology , Thyroid Neoplasms/immunology , Aged , Antibodies/chemistry , Biomarkers, Tumor , Cell Differentiation , DNA Mutational Analysis , Disease Progression , Disease-Free Survival , Female , Humans , Iodine Radioisotopes/pharmacology , Male , Middle Aged , Progression-Free Survival , Prospective Studies , Protein Kinase Inhibitors/therapeutic use , Salvage Therapy , Thyroid Neoplasms/therapy , Treatment Outcome
9.
Clin Cancer Res ; 26(15): 4064-4071, 2020 08 01.
Article in English | MEDLINE | ID: mdl-32321716

ABSTRACT

PURPOSE: Brain involvement occurs in the majority of patients with metastatic melanoma. The potential of circulating tumor DNA (ctDNA) for surveillance and monitoring systemic therapy response in patients with melanoma brain metastases merits investigation. EXPERIMENTAL DESIGN: This study examined circulating BRAF, NRAS, and c-KIT mutations in patients with melanoma with active brain metastases receiving PD-1 inhibitor-based therapy. Intracranial and extracranial disease volumes were measured using the sum of product of diameters, and response assessment performed using RECIST. Longitudinal plasma samples were analyzed for ctDNA over the first 12 weeks of treatment (threshold 2.5 copies/mL plasma). RESULTS: Of a total of 72 patients, 13 patients had intracranial metastases only and 59 patients had concurrent intracranial and extracranial metastases. ctDNA detectability was 0% and 64%, respectively, and detectability was associated with extracranial disease volume (P < 0.01). Undetectable ctDNA on-therapy was associated with extracranial response (P < 0.01) but not intracranial response. The median overall survival in patients with undetectable (n = 34) versus detectable (n = 38) ctDNA at baseline was 39.2 versus 10.6 months [HR, 0.51; 95% confidence interval (CI), 0.28-0.94; P = 0.03] and on-therapy was 39.2 versus 9.2 months (HR, 0.32; 95% CI, 0.16-0.63; P < 0.01). CONCLUSIONS: ctDNA remains a strong prognostic biomarker in patients with melanoma with brain metastases, especially in patients with concurrent extracranial disease. However, ctDNA was not able to detect or monitor intracranial disease activity, and we recommend against using ctDNA as a sole test during surveillance and therapeutic monitoring in patients with melanoma.


Subject(s)
Biomarkers, Tumor/blood , Brain Neoplasms/drug therapy , Circulating Tumor DNA/blood , Immune Checkpoint Inhibitors/therapeutic use , Melanoma/drug therapy , Skin Neoplasms/drug therapy , Aged , Biomarkers, Tumor/genetics , Brain Neoplasms/blood , Brain Neoplasms/mortality , Brain Neoplasms/secondary , Circulating Tumor DNA/genetics , Female , Follow-Up Studies , GTP Phosphohydrolases/blood , GTP Phosphohydrolases/genetics , Humans , Kaplan-Meier Estimate , Longitudinal Studies , Male , Melanoma/blood , Melanoma/mortality , Melanoma/secondary , Membrane Proteins/blood , Membrane Proteins/genetics , Middle Aged , Mutation , Prognosis , Proto-Oncogene Proteins B-raf/blood , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins c-kit/genetics , Risk Assessment/methods , Risk Assessment/statistics & numerical data , Skin Neoplasms/blood , Skin Neoplasms/mortality , Skin Neoplasms/pathology , Treatment Outcome
10.
Nat Protoc ; 15(5): 1628-1648, 2020 05.
Article in English | MEDLINE | ID: mdl-32238953

ABSTRACT

The therapeutic response to immune checkpoint blockade (ICB) is highly variable, not only between different cancers but also between patients with the same cancer type. The biological mechanisms underlying these differences in response are incompletely understood. Identifying correlates in patient tumor samples is challenging because of genetic and environmental variability. Murine studies usually compare different tumor models or treatments, introducing potential confounding variables. This protocol describes bilateral murine tumor models, derived from syngeneic cancer cell lines, that display a symmetrical yet dichotomous response to ICB. These models enable detailed analysis of whole tumors in a highly homogeneous background, combined with knowledge of the therapeutic outcome within a few weeks, and could potentially be used for mechanistic studies using other (immuno-)therapies. We discuss key considerations and describe how to use two cell lines as fully optimized models. We discuss experimental details, including proper inoculation technique to achieve symmetry and one-sided surgical tumor removal, which takes only 5 min per mouse. Furthermore, we outline the preparation of bulk tissue or single-cell suspensions for downstream analyses such as bulk RNA-seq, immunohistochemistry, single-cell RNA-seq and flow cytometry.


Subject(s)
Antineoplastic Agents, Immunological , Drug Screening Assays, Antitumor , Neoplasms, Experimental , Animals , Cell Line, Tumor , Female , Mice , Mice, Inbred BALB C
11.
Front Immunol ; 11: 223, 2020.
Article in English | MEDLINE | ID: mdl-32133005

ABSTRACT

Immune checkpoint blockade (ICB) has revolutionized cancer treatment, providing remarkable clinical responses in some patients. However, the majority of patients do not respond. It is therefore crucial both to identify predictive biomarkers of response and to increase the response rates to immune checkpoint therapy. In this review we explore the current literature about the predictive characteristics of the tumor microenvironment and discuss therapeutic approaches that aim to change this toward a milieu that is conducive to response. We propose a personalized biomarker-based adaptive approach to immunotherapy, whereby a sensitizing therapy is tailored to the patient's specific tumor microenvironment, followed by on-treatment verification of a change in the targeted biomarker, followed by immune checkpoint therapy. By incorporating detailed knowledge of the immunological tumor microenvironment, we may be able to sensitize currently non-responsive tumors to respond to immune checkpoint therapy.


Subject(s)
Immune Checkpoint Inhibitors/therapeutic use , Neoplasms/drug therapy , Tumor Microenvironment , Animals , Biomarkers, Tumor , Humans , Interferon-gamma/physiology , Mice , Microbiota , Neoplasms/blood supply , Neoplasms/immunology , Oncolytic Virotherapy , Precision Medicine , T-Lymphocytes/immunology
12.
Mol Cancer Ther ; 19(2): 460-467, 2020 02.
Article in English | MEDLINE | ID: mdl-31645440

ABSTRACT

Mutations in ERK signaling drive a significant percentage of malignancies. LY3009120, a pan-RAF and dimer inhibitor, has preclinical activity in RAS- and BRAF-mutated cell lines including BRAF-mutant melanoma resistant to BRAF inhibitors. This multicenter, open-label, phase I clinical trial (NCT02014116) consisted of part A (dose escalation) and part B (dose confirmation) in patients with advanced/metastatic cancer. In part A, oral LY3009120 was dose escalated from 50 to 700 mg twice a day on a 28-day cycle. In part B, 300 mg LY3009120 was given twice a day. The primary objective was to identify a recommended phase II dose (RP2D). Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary efficacy. Identification of pharmacodynamic biomarkers was exploratory. In parts A and B, 35 and 16 patients were treated, respectively (N = 51). In part A, 6 patients experienced eight dose-limiting toxicities. The RP2D was 300 mg twice a day. Common (>10%) any-grade drug-related treatment-emergent adverse events were fatigue (n = 15), nausea (n = 12), dermatitis acneiform (n = 10), decreased appetite (n = 7), and maculopapular rash (n = 7). The median duration of treatment was 4 weeks; 84% of patients completed one or two cycles of treatment. Exposures observed at 300 mg twice a day were above the preclinical concentration associated with tumor regression. Eight patients had a best overall response of stable disease; there were no complete or partial clinical responses. Despite adequate plasma exposure levels, predicted pharmacodynamic effects were not observed.


Subject(s)
Neoplasms/drug therapy , Phenylurea Compounds/therapeutic use , Pyrimidines/therapeutic use , Adult , Aged , Aged, 80 and over , Cell Line, Tumor , Female , Humans , Male , Middle Aged , Neoplasm Metastasis , Phenylurea Compounds/pharmacology , Pyrimidines/pharmacology , Young Adult
13.
Sci Transl Med ; 11(501)2019 07 17.
Article in English | MEDLINE | ID: mdl-31316010

ABSTRACT

Cancer immunotherapy using antibodies that target immune checkpoints has delivered outstanding results. However, responses only occur in a subset of patients, and it is not fully understood what biological processes determine an effective outcome. This lack of understanding hinders the development of rational combination treatments. We set out to define the pretreatment microenvironment associated with an effective outcome by using the fact that inbred mouse strains bearing monoclonal cancer cell line-derived tumors respond in a dichotomous manner to immune checkpoint blockade (ICB). We compared the cellular composition and gene expression profiles of responsive and nonresponsive tumors from mice before ICB and validated the findings in cohorts of patients with cancer treated with ICB antibodies. We found that responsive tumors were characterized by an inflammatory gene expression signature consistent with up-regulation of signal transducer and activator of transcription 1 (STAT1) and Toll-like receptor 3 (TLR3) signaling and down-regulation of interleukin-10 (IL-10) signaling. In addition, responsive tumors had more infiltrating-activated natural killer (NK) cells, which were necessary for response. Pretreatment of mice with large established tumors using the STAT1-activating cytokine interferon-γ (IFNγ), the TLR3 ligand poly(I:C), and an anti-IL-10 antibody sensitized tumors to ICB by attracting IFNγ-producing NK cells into the tumor, resulting in increased cure rates. Our results identify a pretreatment tumor microenvironment that predicts response to ICB, which can be therapeutically attained. These data suggest a biomarker-driven approach to patient management to establish whether a patient would benefit from treatment with sensitizing therapeutics before ICB.


Subject(s)
Immunotherapy , Killer Cells, Natural/immunology , STAT1 Transcription Factor/metabolism , Signal Transduction , Tumor Microenvironment/immunology , Animals , Cell Line, Tumor , Cell Proliferation , Clone Cells , Combined Modality Therapy , Disease Models, Animal , Gene Expression Regulation, Neoplastic , Humans , Inflammation/pathology , Mice, Inbred BALB C , Mice, Inbred C57BL , Neoplasms/genetics , Neoplasms/immunology , Neoplasms/pathology , Phenotype
14.
Target Oncol ; 13(1): 89-98, 2018 02.
Article in English | MEDLINE | ID: mdl-29188408

ABSTRACT

BACKGROUND: Delta-like ligand 4-Notch (DLL4-Notch) signaling contributes to the maintenance of chemotherapy-resistant cancer stem cells and tumor vasculature. OBJECTIVE: This phase IB trial of demcizumab, an IgG2 humanized monoclonal antibody directed against DLL4, was undertaken to determine its maximum tolerated dose, safety, immunogenicity, preliminary efficacy, pharmacokinetics, and pharmacodynamics, combined with standard chemotherapy. PATIENTS AND METHODS: Forty-six treatment-naive patients with metastatic non-squamous non-small cell lung cancer (NSCLC) were enrolled in this open-label, dose-escalation study using a standard 6 + 6 design. Demcizumab (2.5, 5.0, and 7.5 mg/kg) was given once every 3 weeks with standard doses of pemetrexed and carboplatin using a continuous (six cycles followed by demcizumab maintenance) or a truncated demcizumab regimen (four cycles followed by pemetrexed maintenance). RESULTS: Initially, continuous demcizumab was given until progression but two patients developed grade 3 pulmonary hypertension and congestive heart failure after eight or more infusions. Thereafter, 23 patients were treated with a truncated regimen of demcizumab, which was not associated with any grade 3 or greater cardiopulmonary toxicity. Common adverse events were hypertension, raised brain natriuretic peptide, and those expected from carboplatin and pemetrexed alone. Twenty of 40 evaluable patients (50%) had objective tumor responses. In peripheral blood, demcizumab treatment modulated the expression of genes regulating Notch signaling and angiogenesis, and achieved concentrations exceeding those saturating DLL4 binding. CONCLUSIONS: This study has identified a truncated dosing regimen and recommended phase II dose of demcizumab (5 mg/kg q3-weekly ×4) for subsequent clinical evaluation in combination with standard carboplatin and pemetrexed chemotherapy. NCT01189968.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Carboplatin/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Pemetrexed/therapeutic use , Adult , Aged , Antibodies, Monoclonal, Humanized/pharmacology , Carboplatin/pharmacology , Carcinoma, Non-Small-Cell Lung/pathology , Female , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Pemetrexed/pharmacology
15.
Nat Rev Drug Discov ; 16(4): 264-272, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28057932

ABSTRACT

Recently, there has been a coordinated effort from academic institutions and the pharmaceutical industry to identify biomarkers that can predict responses to immune checkpoint blockade in cancer. Several biomarkers have been identified; however, none has reliably predicted response in a sufficiently rigorous manner for routine use. Here, we argue that the therapeutic response to immune checkpoint blockade is a critical state transition of a complex system. Such systems are highly sensitive to initial conditions, and critical transitions are notoriously difficult to predict far in advance. Nevertheless, warning signals can be detected closer to the tipping point. Advances in mathematics and network biology are starting to make it possible to identify such warning signals. We propose that these dynamic biomarkers could prove to be useful in distinguishing responding from non-responding patients, as well as facilitate the identification of new therapeutic targets for combination therapy.


Subject(s)
Biomarkers, Tumor , Immune System/drug effects , Molecular Targeted Therapy/methods , Neoplasms/drug therapy , Neoplasms/immunology , Animals , Humans , Nonlinear Dynamics
16.
Clin Cancer Res ; 22(18): 4559-66, 2016 Sep 15.
Article in English | MEDLINE | ID: mdl-27117181

ABSTRACT

PURPOSE: Marizomib (NPI-0052) is an irreversible proteasome inhibitor, derived from a marine actinomycete, with activity and specificity that is distinct from other proteasome inhibitors. EXPERIMENTAL DESIGN: Phase I study (NPI-0052-102) evaluated the MTD, pharmacokinetics, and pharmacodynamics of marizomib intravenously on two dosing schedules. RESULTS: Forty-two patients with advanced malignancies received Schedule A (0.1-0.9 mg/m(2) over 1-10 minutes on days 1, 8, 15 in 4-week cycles); 44 patients with relapsed and/or refractory multiple myeloma (RRMM) and other hematologic malignancies received Schedule B (0.075-0.6 mg/m(2) over 1 minute to 2 hours on days 1, 4, 8, 11, in 3-week cycles). The Schedule A recommended phase II dose was 0.7 mg/m(2) over 10 minutes; Schedule B was 0.5 mg/m(2) over 2 hours. The most common (>25% of patients) related adverse events were fatigue, nausea, diarrhea, and infusion site pain (Schedule A); and fatigue (Schedule B). Overall response rate of 11% was seen in 27 efficacy-evaluable RRMM Schedule B patients (1 very good partial response, 3 partial responses, 4 minimal responses, and 12 stable disease). One Schedule A patient with transformed marginal zone lymphoma had complete response. Marizomib has a short half-life (<30 minutes), with high volume of distribution (∼15-416 L) and clearance (∼0.9-22 L/minutes). CONCLUSIONS: Marizomib does not exhibit the severe peripheral neuropathy or hematologic toxicity observed with other proteasome inhibitors. Marizomib was generally well tolerated with low-dose dexamethasone, demonstrated activity in heavily pretreated RRMM patients, and warrants further evaluation. Clin Cancer Res; 22(18); 4559-66. ©2016 AACR.


Subject(s)
Antineoplastic Agents/therapeutic use , Lactones/therapeutic use , Multiple Myeloma/drug therapy , Multiple Myeloma/pathology , Neoplasms/drug therapy , Neoplasms/pathology , Proteasome Inhibitors/therapeutic use , Pyrroles/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Drug Administration Schedule , Female , Humans , Lactones/administration & dosage , Lactones/adverse effects , Lactones/pharmacokinetics , Male , Middle Aged , Neoplasm Staging , Proteasome Inhibitors/administration & dosage , Proteasome Inhibitors/adverse effects , Proteasome Inhibitors/pharmacokinetics , Pyrroles/administration & dosage , Pyrroles/adverse effects , Pyrroles/pharmacokinetics , Recurrence , Retreatment , Treatment Outcome , Young Adult
17.
Lung Cancer ; 93: 9-16, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26898608

ABSTRACT

OBJECTIVES: The immune effects of EGFR tyrosine kinase inhibitors (EGFR-TKIs) are poorly understood. Identifying immune biomarkers could guide patient selection and optimisation of EGFR-TKI-immunotherapy combinations. MATERIALS AND METHODS: 33 patients with NSCLC treated with an EGFR-TKI were prospectively enrolled. Peripheral blood mononuclear cells were collected pre-treatment, and after 1, 3 and 8 weeks. Flow cytometry was used to identify immune cell subsets, including PD-1 and PD-L1 expressing T cells. Immune parameters were correlated with clinical outcomes. RESULTS: Compared to healthy donors (n=10), patients had higher pre-treatment proportions of proliferating and PD-L1(+)CD3(+) T cells (p<0.001). Compared to patients with an EGFR mutation (n=12), patients without a known mutation (n=21) had higher proportions of proliferating CD4(+) and PD-L1(+)CD3(+) T cells (p=0.03). There was a significant increase in PD-L1(+) T cells after 1 week of EGFR-TKI in patients whose disease progressed compared to non-progressors. Patients with higher PD-L1(+)CD3(+) T cells at 1-week were more likely to progress (OR 30.3, p<0.01) and had shorter PFS (1.6 vs. 8.8m; p<0.01) and OS (3.8 vs 23.2m; p<0.001) than those with fewer PD-L1(+)CD3(+) T cells. On multivariate analysis, high PD-L1(+)CD3(+) T cells was the only independent predictor for PFS (HR 3.7, p=0.01), while for OS independent predictors were high PD-L1(+)CD3(+) T cells (HR 6.5, p<0.01) and EGFR-negative status (HR 3.3, p=0.04). CONCLUSIONS: There was a significant correlation between PD-L1 expression on peripheral T cells and clinical outcomes in EGFR-TKI-treated NSCLC. This warrants further validation as a blood-based biomarker that may identify candidates for PD-1 inhibitors or immunotherapy-EGFR-TKI combinations.


Subject(s)
B7-H1 Antigen/metabolism , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/mortality , Lung Neoplasms/metabolism , Lung Neoplasms/mortality , T-Lymphocytes/metabolism , Aged , Aged, 80 and over , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Biomarkers , Carcinoma, Non-Small-Cell Lung/diagnosis , Carcinoma, Non-Small-Cell Lung/drug therapy , Case-Control Studies , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Female , Humans , Immunophenotyping , Kaplan-Meier Estimate , Lung Neoplasms/diagnosis , Lung Neoplasms/drug therapy , Male , Middle Aged , Mutation , Prognosis , Proportional Hazards Models , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Retreatment , T-Lymphocytes/immunology , Treatment Outcome
18.
Lung Cancer ; 90(1): 55-60, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26259878

ABSTRACT

OBJECTIVES: Malignant pleural mesothelioma (MPM) is a chemotherapy resistant tumor with a poor prognosis. Hypoxia is increasingly recognized as an important factor in tumor aggressiveness and cellular resistance to chemotherapy and radiation treatment. This prospective pilot study was performed with [F-18] fluoromisonidazole (FMISO) PET-CT to characterize hypoxia in patients with MPM. MATERIALS AND METHODS: Twenty prospectively recruited patients with histologically or cytologically confirmed MPM not currently receiving systemic or local treatment underwent both FMISO and fluorodeoxyglucose (FDG) PET-CT scans within 2 weeks. FMISO and FDG PET-CT scans were independently analyzed visually and semi-quantitatively using SUVmax and tumor to background ratio (TBR) in order to assess tumor hypoxia and metabolic activity. Lesion by lesion analysis was performed in sites of measurable pleural masses. RESULTS: Visual analysis demonstrated tumor FMISO activity in 17 of 20 patients, and tumor FDG activity in 19 of 20 patients. Focal areas of bulky tumor were most likely to demonstrate hypoxia. In 19 patients suitable for semi-quantitative analysis the median FDG SUVmax was 6.4 (range 1.9-19.1), median FMISO SUVmax was 2.5 (range 1.4-3.7) and median FMISO TBR was 1.8 (1.1-2.5). There was a positive correlation between intensity of metabolic activity and hypoxia (r=0.72, p=0.001). Lesion by lesion analysis demonstrated a positive correlation between tumor thickness and FMISO activity (r=0.77, p<0.001). CONCLUSION: This pilot study confirms that MPM is a tumor with significant areas of hypoxia, particularly in dominant tumor masses. The relationship of tumor hypoxia to effectiveness of chemotherapy and/or radiation therapy warrants prospective assessment.


Subject(s)
Fluorodeoxyglucose F18/analysis , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/metabolism , Mesothelioma/diagnostic imaging , Mesothelioma/metabolism , Misonidazole/analogs & derivatives , Pleural Neoplasms/diagnostic imaging , Pleural Neoplasms/metabolism , Radiopharmaceuticals/analysis , Aged , Aged, 80 and over , Cell Hypoxia/physiology , Female , Humans , Lung Neoplasms/pathology , Male , Mesothelioma/pathology , Mesothelioma, Malignant , Middle Aged , Misonidazole/analysis , Pilot Projects , Pleural Neoplasms/pathology , Positron-Emission Tomography/methods , Prognosis , Prospective Studies , Tomography, X-Ray Computed/methods
19.
Lung Cancer ; 81(3): 422-427, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23787063

ABSTRACT

BNC105P is a tubulin polymerisation inhibitor that selectively disrupts tumour vasculature and suppresses cancer cell proliferation. This agent has exhibited preclinical and phase I activity in Malignant Pleural Mesothelioma (MPM). This phase II, single arm trial investigated the efficacy and safety of BNC105P as second line therapy in MPM. Participants had progressive MPM after first line pemetrexed/platinum chemotherapy, ECOG PS 0-1, adequate organ function, and measurable disease. BNC105P 16 mg/m(2) was administered intravenously on day 1 and 8 every 21 days until progression or undue toxicity. The primary endpoint was centrally reviewed objective response rate (RR). Tumour response was assessed every two cycles using modified RECIST. 30 patients were enrolled in 10 months, predominantly male (90%), ECOG PS 1 (77%), epithelioid histology (67%), and non-metastatic disease (67%). All patients received at least one dose of study drug, with a median of 2 cycles. No significant haematologic, biochemical, or cardiac adverse events (AEs) were observed. Grade 3 or 4 AEs occurred in 10 patients (33%). There were 2 deaths on study: 1 cardiorespiratory, the other to pneumonia. We observed 1 partial response (3%); 13 patients had stable disease (43%). Median progression free survival was 1.5 months (95% CI 1.4-2.4); median overall survival was 8.2 months (95% CI 3.8-11.9). BNC105P was safe and tolerable. The sole response was insufficient to warrant further research as a single agent.


Subject(s)
Antineoplastic Agents/therapeutic use , Benzofurans/therapeutic use , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Mesothelioma/drug therapy , Mesothelioma/pathology , Organophosphates/therapeutic use , Pleural Neoplasms/drug therapy , Pleural Neoplasms/pathology , Tubulin Modulators/therapeutic use , Adult , Aged , Aged, 80 and over , Benzofurans/administration & dosage , Benzofurans/adverse effects , Biomarkers/blood , Biomarkers/metabolism , Female , GPI-Linked Proteins/blood , GPI-Linked Proteins/metabolism , Humans , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/mortality , Male , Mesothelin , Mesothelioma/diagnostic imaging , Mesothelioma/mortality , Mesothelioma, Malignant , Middle Aged , Neoplasm Staging , Organophosphates/administration & dosage , Organophosphates/adverse effects , Pleural Neoplasms/diagnostic imaging , Pleural Neoplasms/mortality , Radiography , Treatment Outcome , Tubulin Modulators/administration & dosage , Tubulin Modulators/adverse effects , Tumor Burden
20.
J Cancer Educ ; 28(1): 60-5, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23378153

ABSTRACT

A number of curricula have been developed to address shortfalls in cancer education. However, no standardised means of assessing medical graduates against such curricula currently exist. This paper describes the use of expert panels to determine the level of cancer-related knowledge required by junior doctors. Participants individually reviewed knowledge items from the Ideal Oncology Curriculum for Medical Students and rated the level of understanding and specificity of each. On completion, panel sessions were convened to reach consensus. Fifty-two (17 %) items were considered irrelevant for junior doctors, whilst 164 items (54 %) and 85 items (28 %) were deemed appropriate at a moderate and high level of understanding, respectively. As a result, 249 (83 %) of the 301 items were deemed appropriate for junior doctors. Expert panels provide an important insight into the requirements of junior doctors, reduce ambiguity and facilitate discussion, resulting in higher quality data than that produced solely through individual reviews.


Subject(s)
Clinical Competence/standards , Expert Testimony/methods , Health Knowledge, Attitudes, Practice , Medical Staff, Hospital/education , Neoplasms/prevention & control , Australia , Communication , Female , Humans , Male
SELECTION OF CITATIONS
SEARCH DETAIL
...