Clinical trials of MRI-based immune cell imaging: challenges and perspectives

Cancer is one of the leading causes of death worldwide, and current research has focused on the discovery of novel approaches to effectively treat this disease. Recently, a considerable number of clinical trials have demonstrated the success of immunomodulatory therapies for the treatment of cancer. Monoclonal antibodies can target components of the immune system to either i) agonise co-stimulatory molecules, such as CD137, OX40 and CD40; or ii) inhibit immune checkpoints, such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death-1 (PD-1) and its corresponding ligand PD-L1. Although tumour regression is the outcome for some patients following immunotherapy, many patients still do not respond. Furthermore, chemotherapy has been the standard of care for most cancers, but the immunomodulatory capacity of these drugs has only recently been uncovered. The ability of chemotherapy to modulate the immune system through a variety of mechanisms, including immunogenic cell death (ICD), increased antigen presentation and depletion of regulatory immune cells, highlights the potential for synergism between conventional chemotherapy and novel immunotherapy. In addition, recent pre-clinical trials indicate dipeptidyl peptidase (DPP) enzyme inhibition, an enzyme that can regulate immune cell trafficking to the tumour microenvironment, as a novel cancer therapy. The present review focuses on the current immunological approaches for the treatment of cancer, and summarizes clinical trials in the field of immunotherapy as a single treatment and in combination with chemotherapy.

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Self-navigated low-rank MRI for MPIO-labeled immune cell imaging of the heart

2014 36th Annual International Conference of the IEEE Engineering in Medicine and Biology Society ◽

10.1109/embc.2014.6943893 ◽

2014 ◽

Author(s):

Anthony G. Christodoulou ◽

Yijen L. Wu ◽

T. Kevin Hitchens ◽

Chien Ho ◽

Zhi-Pei Liang

Keyword(s):

Cell Imaging ◽

Immune Cell ◽

Low Rank

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Angiogenic and T-effector subgroups identified by gene expression profiling (GEP) and propensity for PBRM1 and BAP1 alterations in clear cell renal cell carcinoma (ccRCC).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.343 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 343-343

Author(s):

Pedro C. Barata ◽

Shuchi Gulati ◽

Andrew Elliott ◽

Arpit Rao ◽

Hans J. Hammers ◽

...

Keyword(s):

Gene Expression ◽

Clinical Trials ◽

Hierarchical Clustering ◽

Immune Cell ◽

Expression Profiles ◽

Gene Expression Signature ◽

Predictive Biomarkers ◽

Primary Tumors ◽

Metastatic Sites ◽

Patient Subgroups

343 Background: With the emergence of multiple active treatment options in RCC, predictive biomarkers for optimal treatment selection are lacking. Gene expression data from IMmotion151 and Javelin Renal 101 clinical trials generated anti-angiogenic and immune signatures that warrant further validation. We aimed to describe the genomic and gene expression profiles in a multi-institutional database of patients with ccRCC, and its association with other biomarkers of interest. Methods: Whole transcriptome sequencing was performed for ccRCC patient samples submitted to a commercial CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ) from February 2019 to September 2020. Tumor GEP and hierarchical clustering based on the validated 66-gene signature (D’Costa et al, 2020) were used to identify patient subgroups. Samples from both primary tumors and metastatic sites were included. Results: A total of 316 patients with ccRCC, median age 62 (range 32-90), 71.8% men, were included. Tissue samples were obtained from primary tumor (46.5%), lung (12.3%), bone (9.5%), liver (4.7%) and other metastatic sites (27%). Gene expression analysis identified angiogenic, mixed and T-effector subgroups in 24.1%, 51.3% and 24.7%, respectively. Patients with angiogenic subgroup tumors compared to those with T-effector subgroup tumors were more likely to be older (63 versus 60 years, p=0.035), female (40.8% versus 16.7%, p=0.0009) and more frequently found in pancreatic/small bowel metastases (75% versus 12.5%, p=0.0103). Biomarkers of potential response to immunotherapy such as PD-L1 (p=0.0021), TMB (not significant), and dMMR/MSI-H status (not significant) were more frequent in the T-effector subgroup. PBRM1 mutations were more common in the angiogenic subgroup (62.0% vs 37.5%, p=0.0034) while BAP1 mutations were more common in the T-effector subgroup (18.6% versus 3.0%, p= 0.0035). Immune cell population abundance (e.g. NK cells, monocytes) and immune checkpoint gene expression (TIM-3, PD-L1, PD-L2, CTLA4) were also increased in the T-effector subgroup. Conclusions: Our hierarchical clustering results based on the 66-gene expression signature were concordant with results from prior studies. Patient subgroups identified by evaluation of angiogenic and T-effector signature scores exhibit significantly different mutations and immune profiles. These findings require prospective validation in future biomarker-selected clinical trials.

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Targeted Tumor Therapy Remixed—An Update on the Use of Small-Molecule Drugs in Combination Therapies

Cancers ◽

10.3390/cancers10060155 ◽

2018 ◽

Vol 10 (6) ◽

pp. 155 ◽

Cited By ~ 26

Author(s):

Martina Gatzka

Keyword(s):

Clinical Trials ◽

Targeted Therapy ◽

Small Molecule ◽

Immune Cell ◽

Checkpoint Inhibitors ◽

Tumor Therapy ◽

Metabolic Reprogramming ◽

Comprehensive Overview ◽

Small Molecule Drugs ◽

Mutational Status

Over the last decade, the treatment of tumor patients has been revolutionized by the highly successful introduction of novel targeted therapies, in particular small-molecule kinase inhibitors and monoclonal antibodies, as well as by immunotherapies. Depending on the mutational status, BRAF and MEK inhibitor combinations or immune checkpoint inhibitors are current first-line treatments for metastatic melanoma. However, despite great improvements of survival rates limitations due to tumor heterogeneity, primary and acquired therapy resistance, immune evasion, and economical considerations will need to be overcome. Accordingly, ongoing clinical trials explore the individualized use of small-molecule drugs in new targeted therapy combinations based on patient parameters and tumor biopsies. With focus on melanoma therapy this review aims at providing a comprehensive overview of such novel alternative and combinational therapy strategies currently emerging from basic research. The molecular principles and drug classes that may hold promise for improved tumor therapy combination regimens including kinase inhibition, induction of apoptosis, DNA-damage response inhibition, epigenetic reprogramming, telomerase inhibition, redox modulation, metabolic reprogramming, proteasome inhibition, cancer stem cell transdifferentiation, immune cell signaling modulation, and others, are explained in brief. In addition, relevant targeted therapy combinations in current clinical trials and individualized treatment strategies are highlighted.

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Bispecific antibodies targeting dual tumor-associated antigens in cancer therapy

Journal of Cancer Research and Clinical Oncology ◽

10.1007/s00432-020-03404-6 ◽

2020 ◽

Vol 146 (12) ◽

pp. 3111-3122

Author(s):

Shuyu Huang ◽

Sander M. J. van Duijnhoven ◽

Alice J. A. M. Sijts ◽

Andrea van Elsas

Keyword(s):

Clinical Trials ◽

Cancer Therapy ◽

Clinical Evaluation ◽

Immune Cell ◽

Early Stage ◽

Relevant Literature ◽

Hematologic Malignancies ◽

Bispecific Antibodies ◽

Tumor Associated Antigens ◽

Tumor Selectivity

Abstract Purpose Bispecific antibodies (BsAbs) have emerged as a leading drug class for cancer therapy and are becoming increasingly of interest for therapeutic applications. As of April 2020, over 123 BsAbs are under clinical evaluation for use in oncology (including the two marketed BsAbs Blinatumomab and Catumaxomab). The majority (82 of 123) of BsAbs under clinical evaluation can be categorized as bispecific immune cell engager whereas a second less well-discussed subclass of BsAbs targets two tumor-associated antigens (TAAs). In this review, we summarize the clinical development of dual TAAs targeting BsAbs and provide an overview of critical considerations when designing dual TAA targeting BsAbs. Methods Herein the relevant literature and clinical trials published in English until April 1st 2020 were searched using PubMed and ClinicalTrials.gov database. BsAbs were considered to be active in clinic if their clinical trials were not terminated, withdrawn or completed before 2018 without reporting results. Data missed by searching ClinicalTrials.gov was manually curated. Results Dual TAAs targeting BsAbs offer several advantages including increased tumor selectivity, potential to concurrently modulate two functional pathways in the tumor cell and may yield improved payload delivery. Conclusions Dual TAAs targeting BsAbs represent a valuable class of biologics and early stage clinical studies have demonstrated promising anti-tumor efficacy in both hematologic malignancies and solid tumors.

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Translational impact of NIH-funded nonhuman primate research in transplantation

Science Translational Medicine ◽

10.1126/scitranslmed.aau0143 ◽

2019 ◽

Vol 11 (500) ◽

pp. eaau0143 ◽

Cited By ~ 1

Author(s):

Stuart J. Knechtle ◽

Julia M. Shaw ◽

Bernhard J. Hering ◽

Kristy Kraemer ◽

Joren C. Madsen

Keyword(s):

Clinical Trials ◽

Cell Therapy ◽

Immune Responses ◽

Nonhuman Primate ◽

Immune Cell ◽

National Institutes Of Health ◽

Primate Research ◽

Costimulation Blockade ◽

Hematopoietic Chimerism ◽

New Treatments

The National Institutes of Health (NIH) has long supported using nonhuman primate (NHP) models for research on kidney, pancreatic islet, heart, and lung transplantation. The primary purpose of this research has been to develop new treatments for down-modulating or preventing deleterious immune responses after transplantation in human patients. Here, we discuss NIH-funded NHP studies of immune cell depletion, costimulation blockade, regulatory cell therapy, desensitization, and mixed hematopoietic chimerism that either preceded clinical trials or prevented the human application of therapies that were toxic or ineffective.

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Comprehensive Immune Monitoring of Clinical Trials to Advance Human Immunotherapy

10.1101/489765 ◽

2018 ◽

Author(s):

Felix J. Hartmann ◽

Joel Babdor ◽

Pier Federico Gherardini ◽

El-Ad D. Amir ◽

Kyle Jones ◽

...

Keyword(s):

Clinical Trials ◽

Biomarker Discovery ◽

Immune Cell ◽

Automated Analysis ◽

Analysis Data ◽

Immune Monitoring ◽

Investigator Bias ◽

Monitoring Technologies ◽

Peripheral Immune Cells ◽

Multiple Samples

SummaryThe success of immunotherapy has led to a myriad of new clinical trials. Connected to these trials are efforts to discover biomarkers providing mechanistic insight and predictive signatures for personalization. Still, the plethora of immune monitoring technologies can face investigator bias, missing unanticipated cellular responses in limited clinical material. We here present a mass cytometry workflow for standardized, systems-level biomarker discovery in immunotherapy trials. To broadly enumerate human immune cell identity and activity, we established and extensively assessed a reference panel of 33 antibodies to cover major cell subsets, simultaneously quantifying activation and immune checkpoint molecules in a single assay. The resulting assay enumerated ≥ 98% of peripheral immune cells with ≥ 4 positively identifying antigens. Robustness and reproducibility were demonstrated on multiple samples types, across research centers and by orthogonal measurements. Using automated analysis, we monitored complex immune dynamics, identifying signatures in bone-marrow transplantation associated graft-versus-host disease. This validated and available workflow ensures comprehensive immunophenotypic analysis, data comparability and will accelerate biomarker discovery in immunomodulatory therapeutics.

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Programmed Cell Death 1 (PD-1) Ligand (PD-L1) Expression in Solid Tumors As a Predictive Biomarker of Benefit From PD-1/PD-L1 Axis Inhibitors: A Systematic Review and Meta-Analysis

JCO Precision Oncology ◽

10.1200/po.16.00030 ◽

2017 ◽

pp. 1-15 ◽

Cited By ~ 25

Author(s):

Monica Khunger ◽

Adrian V. Hernandez ◽

Vinay Pasupuleti ◽

Sagar Rakshit ◽

Nathan A. Pennell ◽

...

Keyword(s):

Clinical Trials ◽

Cell Death ◽

Programmed Cell Death ◽

Solid Tumors ◽

Immune Cell ◽

Meta Analysis ◽

Objective Response ◽

Small Cell Lung ◽

Programmed Cell Death 1 ◽

Tumor Types

Purpose Drugs targeting the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway show significant clinical activity across several tumor types. However, a majority of patients do not respond to these agents. Use of biomarker assays to predict response to these agents is an active area of research; however, the predictive value of PD-L1 immunohistochemistry (IHC) assays is largely inconsistent across clinical trials. In this meta-analysis of clinical trials of PD-1/PD-L1–targeted agents, we evaluate the predictive value of a tumor and tumor-infiltrating immune cell PD-L1 IHC assay as a biomarker for objective response to PD-1/PD-L1 inhibitors. Methods We searched databases (PubMed, Medline, ASCO abstracts, European Society for Medical Oncology abstracts, and Scopus) up until December 2016 for clinical trials using PD-1/PD-L1 inhibitors with reported PD-L1 biomarker data. Objective response rates (primary end point) from all phase I to III trials investigating nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab in advanced solid tumors were collected. Odds ratios (ORs) for response in PD-L1–positive patients compared with PD-L1–negative patients were calculated using the DerSimonian-Laird random effects model to combine trials. We performed meta-analysis as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results Forty-one distinct trials with 6,664 patients were identified. PD-L1 expression was predictive of favorable response across all tumor types (OR, 2.26; 95% CI, 1.85 to 2.75; P < .001), with the significantly largest effect observed in non–small-cell lung cancer (OR, 2.51; 95% CI, 1.99 to 3.17; P < .001). A subgroup analysis across all non–small-cell lung cancer trials using nivolumab and Dako clone 28-8 (Dako, Carpinteria, CA) IHC antibody assay yielded a significantly higher objective response rate in patients with tumor PD-L1 expression even at the minimum cutoff value of 1% (OR, 2.17; 95% CI, 1.03 to 4.57). Conclusion Our meta-analysis shows that tumor and tumor-infiltrating immune cell PD-L1 overexpression based on IHC is associated with significantly higher response rates to PD-1/PD-L1 axis inhibitors across a range of malignant solid tumors.

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Magnetic-Assisted Treatment of Liver Fibrosis

Cells ◽

10.3390/cells8101279 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1279 ◽

Cited By ~ 9

Author(s):

Kateryna Levada ◽

Alexander Omelyanchik ◽

Valeria Rodionova ◽

Ralf Weiskirchen ◽

Matthias Bartneck

Keyword(s):

Clinical Trials ◽

Liver Fibrosis ◽

Conformational Changes ◽

Metabolic Regulation ◽

Magnetic Particles ◽

Cell Activation ◽

Immune Cell ◽

Single Cells ◽

Nonalcoholic Fatty Liver ◽

Magnetic Forces

Chronic liver injury can be induced by viruses, toxins, cellular activation, and metabolic dysregulation and can lead to liver fibrosis. Hepatic fibrosis still remains a major burden on the global health systems. Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are considered the main cause of liver fibrosis. Hepatic stellate cells are key targets in antifibrotic treatment, but selective engagement of these cells is an unresolved issue. Current strategies for antifibrotic drugs, which are at the critical stage 3 clinical trials, target metabolic regulation, immune cell activation, and cell death. Here, we report on the critical factors for liver fibrosis, and on prospective novel drugs, which might soon enter the market. Apart from the current clinical trials, novel perspectives for anti-fibrotic treatment may arise from magnetic particles and controlled magnetic forces in various different fields. Magnetic-assisted techniques can, for instance, enable cell engineering and cell therapy to fight cancer, might enable to control the shape or orientation of single cells or tissues mechanically. Furthermore, magnetic forces may improve localized drug delivery mediated by magnetism-induced conformational changes, and they may also enhance non-invasive imaging applications.

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