AACR, Author Interviews, Cancer Research / 18.04.2023
AACR23: Phase 1 trial of IO-108, an antagonist antibody targeting LILRB2 (ILT4), as monotherapy and in combination with pembrolizumab in adult patients with advanced relapsed or refractory solid tumors
MedicalResearch.com Interview with:
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Dr. Taylor[/caption]
Matthew H. Taylor, MD
Earle A. Chiles Research Institute
Providence Cancer Institute
Portland, OR
MedicalResearch.com: What is the background for this study? What is the importance of ILT4 or LILRB2 in tumor growth?
Dr. Taylor[/caption]
Matthew H. Taylor, MD
Earle A. Chiles Research Institute
Providence Cancer Institute
Portland, OR
MedicalResearch.com: What is the background for this study? What is the importance of ILT4 or LILRB2 in tumor growth?
- ILT4, also known as LILRB2, is expressed on myeloid cells, including monocytes, DCs, macrophages and neutrophils. LILRB2 expressing myeloid cells promote tumor immune evasion and contribute to anti-PD1 resistance, making this a promising target to reverse myeloid-mediated immune suppression in the TME.
- IO-108 is a fully human IgG4 therapeutic antibody that binds to LILRB2 with high affinity and specificity, and blocks binding of LILRB2 to multiple cancer-relevant ligands. This blockade causes re-programming of immune suppressive myeloid cells to pro-inflammatory in the tumor microenvironment leading to the activation of T cells.
- This first-in-human, open-label Phase 1 study of IO-108 as monotherapy or in combination with pembrolizumab was designed to learn about safety, tolerability and preliminary efficacy of IO-108 as monotherapy or in combination with a PD-1 inhibitor in patients with advanced, metastatic solid tumors. The study was also designed to find a dose of IO-108 that is safe and efficacious to be tested in patients with various solid tumors.
Edward Liu[/caption]
Edward Liu, BA
Second year medical student
Department of Medical Education
Geisinger Commonwealth School of Medicine
Scranton, PA
Medicalresearch.com: What is the background for this study?
Response: The United States’ opioid epidemic continues to rise because of increasing opioid use and availability, contributing to prescription opioid misuse, mortality, and rising cost.1 The worsening health and economic impact of opioid use disorder in the US warrants further attention on the adverse effects and distribution pattern of commonly prescribed opioids like oxycodone (OxyContin), fentanyl (Duragesic), and morphine (MS-Contin). Using the Automated Reports and Consolidated Ordering System (ARCOS) database,2 a comprehensive data collection system of pharmacies and hospitals distribution of Schedule II and III controlled substances in the US with the FDA Adverse Event Reporting System (FAERS)3 has never been done before. This approach may provide a more complete picture of the risks of prescription opioids which can include drowsiness, nausea, and potentially fatal respiratory depression.
Prof. Hamdy[/caption]
Freddie C. Hamdy FRCS, FMedSci
Nuffield Professor of Surgery, University of Oxford
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Prof. Donovan[/caption]
Jenny L. Donovan PhD, FMedSci
Professor of Social Medicine, University of Bristol
MedicalResearch.com: What is the background for this study?
Response: Prostate cancer is a common malignancy in men. Prostate cancer diagnosis is made largely through opportunistic screening with a PSA (Prostate Specific Antigen) blood test, followed by prostate biopsies. The ProtecT study, funded by the National Institute for Health and Care Research in the UK, is the largest randomised trial of treatment in screen-detected localised prostate cancer. The study began by testing 82,429 men between the ages of 50 and 69 years, across nine UK centres with a PSA blood test, followed by biopsies of the prostate if the PSA level was elevated. 2,664 men with clinically localised prostate cancer were found. From these, 1,643 (62%) agreed to be randomised to Surgery (radical prostatectomy to remove the prostate gland), Radiotherapy (external beam with a period of hormone treatment beforehand), or Active Monitoring (where men received regular checks and further investigations, with change to radical treatment as necessary). The men were carefully followed up for an average of 15 years. In parallel, the side-effects of treatments and quality of life of these men was investigated using patient-reported outcomes included in an annual study questionnaire completed for at least 12 years.
Dr. Tauscher-Wisniewski,[/caption]
Sitra Tauscher-Wisniewski, MD
Vice President Clinical Development & Analytics
Novartis Gene Therapies
MedicalResearch.com: What is the background for this study? Would you briefly describe the condition of Spinal muscular atrophy (SMA)?
Response: At the 2023 Muscular Dystrophy Association Conference, we presented new data from two of our Long-Term Follow-Up (LTFU) studies, LT001 and LT002, which show the continued efficacy and durability of Zolgensma across a range of patient populations, with an overall benefit-risk profile that remains favorable. LT001 is a 15-year ongoing observational LTFU study following the Phase 1 START patients, who were the very first patients to receive our gene replacement therapy. LT-002 is a voluntary Phase 4 15-year ongoing follow-up safety and efficacy study of Zolgensma IV and investigational intrathecal (IT) OAV101 in patients previously treated in the Phase 3 IV studies (STR1VE-US, STR1VE-EU, STR1VE-AP, SPR1NT) and the Phase 1 IT study (STRONG).
Spinal muscular atrophy (SMA) is a rare, devastating genetic disease that leads to progressive muscle weakness, paralysis, and when left untreated in one of its most severe forms (SMA Type 1), permanent ventilation or death in 90% of cases by age 2. It is caused by a lack of a functional survival motor neuron 1 (SMN1) gene, and in the most severe forms results in the rapid and irreversible loss of motor neurons, affecting muscle functions, including breathing, swallowing and basic movement.
Dr. Potter[/caption]
MedicalResearch.com Interview with:
Kelly Potter, PhD, RN, CNE
T32 Postdoctoral Scholar
CRISMA Center, Department of Critical Care Medicine
University of Pittsburgh
MedicalResearch.com: What is the background for this study?
Response: While it is well-recognized that survivors of critical illness often experience persistent problems with mental, cognitive, and physical health, very little is known about how these problems (collectively known as post-intensive care syndrome (PICS)) affect resumption of meaningful activities, such as driving.
Dr. Levin[/caption]
Trevor Levin Ph.D.
Founder and CEO of Convergent Genomics that produces the Uroamp assay
San Francisco, CA
MedicalResearch.com: What is the background for this study?
Response: Bladder cancer is one of the most expensive and challenging to diagnose and treat. Therefore, identifying cost-effective urine bladder cancer biomarkers to complement or replace the gold-standard invasive and costly cystoscopy for the early detection and monitoring of this highly recurrent disease is crucial. At the international Agency for research on Cancer (IARC-WHO), we have developed a simple urine-based assay TERT promoter mutations, the most common mutations in bladder cancer, and showed that the urine biomarker could detect bladder cancer patients at diagnosis but many years prior to clinical diagnosis. However, in this study, we wanted to see whether a more comprehensive genomic profiling of urine samples collected years prior to clinical diagnosis of bladder cancer could identify even more patients before they develop any symptoms.
The study was based on the UroAmp test, a general urine test that identifies mutations in 60 genes, developed by the Oregon Health Science University spin out company, Convergent Genomics. Drawing on previous research to identify genetic mutations linked to bladder cancer, the research team narrowed the new test down to focus on mutations within just ten genes.
Working with colleagues from the Tehran University of Medical Sciences in Iran, they trialled the potential new test using samples from the Golestan Cohort Study, which has tracked the health of more than 50,000 participants over ten years, all of whom provided urine samples at recruitment. Forty people within the study developed bladder cancer during that decade, and the team were able to test urine samples from twenty-nine of them, along with samples from 98 other similar participants as controls.
Dr. D'Orsogna[/caption]
Maria-Rita D'Orsogna Ph.D.
Professor, Mathematics
California State University, Northridge
Adjunct Associate Professor
Department of Computational Medicine at UCLA
MedicalResearch.com: What is the background for this study?
Response: Drug overdose deaths have been increasing in the USA for the past two decades. A ‘third wave’ of overdose fatalities started in 2013, with a shift from prescription opioids towards synthetic ones, in particular illicit fentanyl.
To examine trends in drug overdose deaths by gender, race and geography in the United States during the period 2013-2020, we used an epidemiological database provided by the Centers for Disease Control and Prevention, extracting rates by race and gender in all 50 states plus the District of Columbia. We considered the impact of four main drug categories psychostimulants with addiction potential such as methamphetamines; heroin; prescription opioids and synthetic opioids such as fentanyl and its derivatives.
Dr. Koh[/caption]
Andrew Y. Koh, M.D.
Associate Professor, Pediatrics and Microbiology
Prof. Rahimi[/caption]
Kazem Rahimi FRCP, DM, MSc, FESC
Professor of Cardiovascular Medicine and Population Health
University of Oxford
Consultant cardiologist
Oxford University Hospitals NHS Trust
MedicalResearch.com: What is the background for this study?
Response: The prevalence of hypertension has been rising worldwide. To mitigate the burden, identifying the modifiable environmental risk factors of hypertension and developing preventive interventions constitute important public health priorities. Despite the biological plausibility of the link between road traffic noise and the risk of hypertension, the quality of relevant evidence has been low, and the role of air pollution has been uncertain.
Dr. Keyes[/caption]
Dr Helen Keyes
Dr. Mosley[/caption]
Jonathan Mosley, MD, PhD
Associate Professor
Division of Clinical Pharmacology
Departments of Internal Medicine and Biomedical Informatics
Vanderbilt University Medical Center
MedicalResearch.com: What is the background for this study?
Response: Prostate cancer is an important source of morbidity and mortality among men. Earlier detection of disease is essential to reduce these adverse outcomes. Prostate cancer is heritable, and many single nucleotide polymorphisms (SNPs) associated with disease risk have been identified. Thus, there is considerable interest in using tools such as polygenic risk scores, which measure the burden of genetic risk variants an individual carries, to identify men at elevated risk of disease.
Dr. Tsirigos[/caption]
Aristotelis Tsirigos, Ph.D.
Professor of Medicine and Pathology
Co-director, Precision Medicine
Director, Applied Bioinformatics Laboratories
Dr. Kleiman[/caption]
Norman Kleiman, PhD, MS
Department of Environmental Health Sciences
Mailman School of Public Health
Columbia University, New York, NY
MedicalResearch.com: What is the background for this study?
Response: The 1986 Chornobyl nuclear disaster caused the evacuation of 300,000 persons from the cities and villages surrounding the nuclear power plant complex. Pets and belongings were left behind, and the Soviet authorities ordered all animals within the Chornobyl Exclusion Zone killed. Some dogs evaded destruction, and some 300+ descendants of these animals live primarily at two locations today, immediately surrounding the Nuclear Power Plant (NPP) complex and about 10 km away in Chornobyl city. What is relatively unknown to the general public is that Chornobyl is not a desolate, abandoned wasteland. Some thousands of individuals work there every day in continuing cleanup activities and at two new fuel reprocessing facilities built near the damaged reactor. These areas have been substantially remediated, and the average radiation levels are relatively modest. The dogs, which, while feral, are accustomed to human interaction, live near the workers and are not currently exposed to high radiation levels. In contrast to lower radiation levels, there is a toxic mixture of heavy metals, organics, pesticides, and unknown chemicals left over from years’ long cleanup efforts and the decay of a large former military-industrial complex at the NPP.
Since 2016, the NPP authorities have brought in teams of veterinarians and volunteers to spay, neuter, and vaccinate the dogs to protect the workers and deal with a growing population. At the same time, some scientists joined the teams to obtain various kinds of biospecimens (hair, urine, feces, blood, saliva, parasites) to examine the animals’ health and learn how this toxic environment may have affected them or their offspring. Since dogs are human companion animals and live closely with us, any information we learn about health risks to the dogs may be relevant to protecting human workers and inform us about the kinds of health risks posed by ecological and environmental disasters in the future.
Dr. Roca[/caption]
Anna Roca PhD
MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine
Fajara, The Gambia
MedicalResearch.com: What is the background for this study?
Response: Context specific interventions are needed to decrease the high burden of severe neonatal morbidity and mortality in sub-Saharan Africa. Severe bacterial infections are a main cause of neonatal mortality in the continent. Oral intra-partum azithromycin is a cheap intervention easily scalable. Before embarking on this trial, we conducted a proof-of-concept trial that showed the intervention reduced maternal and neonatal bacterial carriage of the most prevalent bacteria causing neonatal sepsis in the continent.
Dr. Khullar[/caption]
Dhruv Khullar, M.D., M.P.P.
Director of Policy Dissemination
Physicians Foundation Center for Physician Practice and Leadership
Assistant Professor of Health Policy and Economics
Weill Cornell Medicine, NYC
MedicalResearch.com: What is the background for this study?
Response: From prior research, we know that there are racial/ethnic differences in the acute impact of COVID-19, including higher rates of hospitalization and death among Black and Hispanic individuals compared to white individuals. Less is known about whether there are differences in the rates or types of long COVID by race and ethnicity.
Alexia Aguilar[/caption]
Alexia Aguilar
Geisinger Commonwealth School of Medicine
Scranton, PA
MedicalResearch.com: What is the background for this study?
Response: Traditional antidepressants like Zoloft and Lexapro have three major drawbacks.
Dr. Martens[/caption]
Christopher R. Martens PhD
Assistant Professor
Director, Delaware Center for Cognitive Aging Research
Department of Kinesiology & Applied Physiology
University of Delaware
Newark, DE
MedicalResearch.com: What is the background for this study?
Response: One of the main issues with Alzheimer's disease is an impaired ability to make energy in the brain. NAD+ is critically involved in the creation of energy within cells and there is strong evidence that nicotinamide riboside (NR), a precursor to NAD+, can restore brain function in mice that exhibit similar characteristics as people with Alzheimer's disease.
We had previously studied the effects of NR in healthy older adults and wanted to see whether it is even capable of getting into brain tissue. We used remaining blood samples from our original study and measured the amount of NAD+ within tiny "vesicles" in the blood that we are quite confident originated from the brain and other neural tissue