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Thursday, January 13, 2022

Nanoparticle Therapeutic Enhances Cancer Immunotherapy

​Researchers at Wake Forest School of Medicine have discovered that a nanoparticle therapeutic enhances cancer immunotherapy and is a possible new approach in treating malignant pleural effusion (MPE). MPE is the accumulation of fluid between the chest wall and lungs and is accompanied by malignant cells and/or tumors. Results from the study were published in Nature Nanotechnology (2021; doi: 10.1038/s41565-021-01032-w).

There are more than 200,000 new cases of MPE in the United States each year, and non-small cell lung cancer accounts for more than one-third of cases.

"MPE is indicative of late-stage metastatic cancer and is associated with a poor prognosis with an average survival of only 4-9 months," said Dawen Zhao, MD, PhD, Associate Professor of Biomedical Engineering at Wake Forest School of Medicine. "MPE can also severely impact quality of life as it causes breathlessness, pain, weight loss, and reduced physical activity."

According to Zhao, recent clinical trials involving immune checkpoint inhibitors (ICI) or novel immunotherapies such as anti-PD-1 have shown some encouraging data in patients with MPE. However, only a small number of MPE patients benefit from immunotherapy and many experience immunotoxicity.

"Clinical evidence also suggests that MPE comprises abundant tumor-associated immune cells that prevent the body's immune system from recognizing and eliminating the cancer," Zhao said. "This 'cold' immune environment could be a major contributor to the failure of ICI."

To mitigate the immune “cold" MPE, Zhao and his team developed a nanoparticle called liposomal cyclic dinucleotide (LNP-CDN) for targeted activation of an immune pathway called STING, which reprograms tumor-associated immune cells to active anti-tumor ones. MPE is often associated with two distinct compartments within the tumor microenvironment, the effusion and also pleural tumors, which co-exist within the pleural cavity. These two distinct compartments make therapeutic interventions and drug delivery challenging.

Upon intrapleural injection in a mouse model, the “cold" immune environment lessened in not only the effusion space, but also within the tumors. Zhao's team combined LNP-CDN with an anti-PD-L1 immunotherapy, which drastically reduced the volume of MPE and inhibited tumor growth in both the pleural cavity and lung tissue in mice with MPE, resulting in prolonged survival.

Zhao's team also tested the nanoparticle therapeutic on human MPE tissue samples, and similar effects were observed—enhanced tumor cell killing by cytotoxic immune cells.

"Administered alone or with immunotherapy, this study demonstrates a possible treatment for MPE," Zhao said. "Given the current prognosis of MPE patients, new interventions are needed to not only prolong survival, but also to improve quality of life."​

Wednesday, January 12, 2022

Decline in Lung Cancer Deaths Linked to Screening, Earlier Diagnosis, & Surgery

​A recent, substantial decline in lung cancer deaths is associated with earlier diagnosis of lung cancer than in the past, supporting the need for increased use of screening to save lives, according to a Mount Sinai study published in JAMA Network Open 2021; doi:10.1001/jamanetworkopen.2021.37508).

The earlier detection of lung cancer came about both due to increased screening via computed tomography (CT) and follow-up on potential cancers found on scans meant to study other organs or disease. Once these precancerous and early-cancer nodules are found, they can be removed with surgery, which can often be curative, according to the study.

“This is the first time a large population-based study has demonstrated decreased lung cancer mortality with early detection—finding cancer in earlier stages—when tumors are smaller and more curable," said the study's lead author Raja M. Flores, MD, Chair of Thoracic Surgery at Mount Sinai Health System and Steven and Ann Ames Professor in Thoracic Surgery at the Icahn School of Medicine at Mount Sinai. “This study emphasizes the impact of screening followed by surgical intervention to save lives in people at high risk for lung cancer."

Lung cancer is diagnosed in more than 200,000 people annually and remains one of the leading causes of cancer deaths in the U.S. Smoking cessation programs after the landmark 1964 Surgeon General's report on smoking and tobacco use have historically contributed to some decline of lung cancer incidence, but experts know that more needs to be done to quell the deadly disease. While prior studies have explored the association of smoking cessation, earlier interventions, and targeted therapies with non-small cell lung cancer mortality, the role of diagnosis at earlier stages due to early detection has not been adequately studied until now.

The findings were based on a retrospective analysis of 312,382 patients with non-small cell lung cancer, which accounts for the vast majority of lung cancer cases, from the Surveillance, Epidemiology, and End Results (SEER) Program, an authoritative source for cancer statistics. Using data from 2006 to 2016, researchers found that, on average, lung cancer deaths decreased by about 4 percent each year.

During the same time period, early-stage diagnoses rose from 26.5 percent to 31.2 percent while late-stage diagnoses decreased from 70.8 to 66.1. Both are considered significant shifts, underlined by their resulting survival rates: the median length of survival for patients with early-stage lung cancer was 57 months while the median for late-stage cancer was 7 months.

In 2013, during the study period, the U.S. Preventive Services Task Force (USPSTF) recommended that at-risk individuals be screened annually for lung cancer via CT. CT scans find cancer in 24.2 percent of scans, while the previous modality of screening, chest X-rays, only found cancer 6.9 percent of the time.

“These findings in context with prior studies seem to suggest that awareness of CT lung cancer screening is associated with an earlier detection of non-small cell lung cancer, but unfortunately, patient adherence to the USPSTF guidance on lung cancer screening with low-dose CT remains low, at around 5 percent of those people who meet the criteria," said study author Emanuela Taioli, MD, PhD, Director of the Institute for Translational Epidemiology and Associate Director for Population Science at The Tisch Cancer Institute at Mount Sinai. “That means that we cannot only attribute CT screening to decreased mortality, but our findings reinforce the importance of screening in the early detection, intervention, and effective treatment of cancer."

Claudia Henschke, MD, PhD, Professor of Diagnostic, Molecular, and Interventional Radiology at the Icahn School of Medicine at Mount Sinai, leads one of the largest lung cancer screening programs in the U.S. and oversees an international registry of more than 80,000 lung cancer screening patients. She said this study underscores the need to ensure that people who are eligible for screening receive it and that research is conducted to investigate our ability to expand who may be eligible given the increase in nonsmoking lung cancer patients whose cancer is largely found in later stages.

“If all people who were eligible to be screened received the low-dose CT scan, which has a dose of radiation comparable to an annual mammogram, we could save up to 80 percent of those people," Dr. Henschke said. “Our lung cancer screening program is open to all people at risk of lung cancer, anyone who is 40 and older whether they are never-smokers, current smokers or former smokers."​

Wednesday, January 12, 2022

​A Blood Test to Predict Who May Benefit From Lung Cancer Screening

A blood test, combined with a risk model based on an individual's history, more accurately determines who is likely to benefit from lung cancer screening than the current U.S. recommendation, according to a study published in the Journal of Clinical Oncology led by researchers from The University of Texas MD Anderson Cancer Center.

A personalized lung cancer risk assessment, combining a blood test based on a four-marker protein panel developed at MD Anderson and an independent model (PLCOm2012) that accounts for smoking history, was more sensitive and specific than the 2021 and 2013 U.S. Preventive Services Task Force (USPSTF) criteria. The study included participants from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial with at least a 10 pack-year smoking history. If implemented, the blood test plus model would have identified 9.2 percent more lung cancer cases for screening and reduced referral to screening among non-cases by 13.7 percent compared to the 2021 USPSTF criteria.

“We recognize that a small percentage of people who are eligible for lung cancer screening through an annual low-dose CT scan are actually getting screening. Moreover, CT screening is not readily available in most countries. So, our goal, for many years, has been to develop a simple blood test that can be used first to determine need for screening and make screening for lung cancer that much more effective," said Sam Hanash, MD, PhD, Professor of Clinical Cancer Prevention and leader of the McCombs Institute for the Early Detection and Treatment of Cancer. “Our study shows for the first time that a blood test could be useful to determine who may benefit from lung cancer screening."

The USPSTF recommends that adults at high risk for lung cancer receive a low-dose CT scan each year, which was shown to reduce lung cancer deaths in the 2011 National Lung Screening Trial. The 2021 USPSTF criteria applies to adults age 50-80 who have at least a 20 pack-year smoking history and currently smoke or have quit within the past 15 years.

Hanash and colleagues developed a blood test incorporating biomarkers that they previously identified as predictive of lung cancer risk. A multicenter team used a blinded study to evaluate the performance of this four-protein marker panel in combination with the PLCOm2012 model, which was independently developed and validated to predict a 6-year risk for lung cancer among individuals who currently smoke or smoked formerly.
“When we began work on a blood test, there were many different types of markers," Hanash said. “We've done multiple analyses over the past decade to come up with a cost-effective test that's simple, yet robust, which has been the guiding principle of our research."

To test the combination of blood markers with the PLCOm2012 model, the researchers analyzed more than 10,000 biospecimens from the PLCO study, including 1,299 blood samples collected from 552 individuals who developed lung cancer and 8,709 samples collected from 2,193 people who did not develop lung cancer.

Among individuals with at least a 10 pack-year smoking history, the combined blood test with PLCOm2012 model showed overall improved sensitivity (88.4% vs. 78.5%) and improved specificity (56.2% vs. 49.3%), compared to the current USPSTF criteria. If implemented, the combined personalized risk assessment would have identified 105 of the 119 people in the PLCO intervention arm who received a lung cancer diagnosis within 1 year.

“A blood test would identify people who could benefit from lung cancer screening but are not eligible today," Hanash said. “Tens of millions of people worldwide could benefit from lung cancer screening. If you can improve screening eligibility by even 5 percent, that is incredibly impactful."

While the blood test could be implemented as a lab-developed test in the near future, FDA approval likely would require evaluation through a prospective clinical trial. ​

Tuesday, December 21, 2021

Differences in T Cells' Functional State Determine Resistance to Cancer Therapy

​Some patients with non-small cell lung cancer (NSCLC) receive a therapy called immune checkpoint blockade (ICB) that helps kill cancer cells by reinvigorating T cells, which are "exhausted" and have stopped working. However, only about 35 percent of NSCLC patients respond to ICB therapy.

Stefani Spranger's lab at the MIT Department of Biology explores the mechanisms behind this resistance, with the goal of inspiring new therapies to better treat NSCLC patients. In a new study published in Science Immunology, a team led by Spranger lab postdoc Brendan Horton, PhD, revealed what causes T cells to be non-responsive to ICB—and suggests a possible solution (2021; doi: 10.1126/sciimmunol.abi8800).

Scientists have long thought that the conditions within a tumor were responsible for determining when T cells stop working and become exhausted after being overstimulated or working for too long to fight a tumor. That's why physicians prescribe ICB to treat cancer—ICB can invigorate the exhausted T cells within a tumor. However, Horton's new experiments show that some ICB-resistant T cells stop working before they even enter the tumor. These T cells are not actually exhausted, but rather they become dysfunctional due to changes in gene expression that arise early during the activation of a T cell, which occurs in lymph nodes. Once activated, T cells differentiate into certain functional states, which are distinguishable by their unique gene expression patterns.

The notion that the dysfunctional state that leads to ICB resistance arises before T cells enter the tumor is quite novel, noted Spranger, the Howard S. and Linda B. Stern Career Development Professor, a member of the Koch Institute for Integrative Cancer Research, and the study's senior author.

"We show that this state is actually a preset condition, and that the T cells are already non-responsive to therapy before they enter the tumor," she stated. As a result, she explained, ICB therapies that work by reinvigorating exhausted T cells within the tumor are less likely to be effective. This suggests that combining ICB with other forms of immunotherapy that target T cells differently might be a more effective approach to help the immune system combat this subset of lung cancer.

In order to determine why some tumors are resistant to ICB, Horton and the research team studied T cells in murine models of NSCLC. The researchers sequenced messenger RNA from the responsive and non-responsive T cells in order to identify any differences between the T cells.

Supported in part by the Koch Institute Frontier Research Program, they used a technique called Seq-Well, developed in the lab of fellow Koch Institute member J. Christopher Love, PhD, the Raymond A. (1921) and Helen E. St. Laurent Professor of Chemical Engineering and a co-author of the study. The technique allows for the rapid gene expression profiling of single cells, which permitted Spranger and Horton to get a very granular look at the gene expression patterns of the T cells they were studying.

Seq-Well revealed distinct patterns of gene expression between the responsive and non-responsive T cells. These differences, which are determined when the T cells assume their specialized functional states, may be the underlying cause of ICB resistance.

Now that Horton and his colleagues had a possible explanation for why some T cells did not respond to ICB, they decided to see if they could help the ICB-resistant T cells kill the tumor cells. When analyzing the gene expression patterns of the non-responsive T cells, the researchers had noticed that these T cells had a lower expression of receptors for certain cytokines, small proteins that control immune system activity. To counteract this, the researchers treated lung tumors in murine models with extra cytokines. As a result, the previously non-responsive T cells were then able to fight the tumors—meaning that the cytokine therapy prevented, and potentially even reversed, the dysfunctionality.

Administering cytokine therapy to human patients is not currently safe, because cytokines can cause serious side effects as well as a reaction called a "cytokine storm," which can produce severe fevers, inflammation, fatigue, and nausea. However, there are ongoing efforts to figure out how to safely administer cytokines to specific tumors. In the future, Spranger and Horton suspect that cytokine therapy could be used in combination with ICB.

"This is potentially something that could be translated into a therapeutic that could increase the therapy response rate in non-small cell lung cancer," Horton noted.
Spranger agrees that this work will help researchers develop more innovative cancer therapies, especially because researchers have historically focused on T-cell exhaustion rather than the earlier role that T-cell functional states might play in cancer.

"If T cells are rendered dysfunctional early on, ICB is not going to be effective, and we need to think outside the box," she said. "There's more evidence, and other labs are now showing this as well, that the functional state of the T cell actually matters quite substantially in cancer therapies." To Spranger, this means that cytokine therapy "might be a therapeutic avenue" for NSCLC patients beyond ICB.

Jeffrey Bluestone, PhD, the A.W. and Mary Margaret Clausen Distinguished Professor of Metabolism and Endocrinology at the University of California-San Francisco, who was not involved with the paper, agrees. "The study provides a potential opportunity to 'rescue' immunity in the NSCLC non-responder patients with appropriate combination therapies," he noted.​

Tuesday, December 21, 2021

​Cholesterol Metabolism in Macrophages Offers Insight Into Lung Cancer

Significant changes in lipid metabolism are known to occur in cells associated with non-small cell lung carcinoma (NSCLC). Alexandra K. Kiemer, PhD, Professor of Pharmaceutical Biology, and Jessica Hoppstädter, researchers at the Saarland University have discovered that the lipid and cholesterol metabolism of immune cells that collaborate with the tumor is severely compromised—in contrast to what is observed in the tumor tissue itself. The cell culture model they developed has allowed them to examine parameters that correlate with tumor growth. The goal now is to find new therapeutic approaches. The research team published its findings in the journal EBioMedicine (2021; doi: 10.1016/j.ebiom.2021.103578).

Lung cancer is the cancer with the highest global mortality rate. This is due in part to the fact that we still do not know what exactly happens in the body when a lung carcinoma forms. Highly complex processes and reaction chains occur within the cells, with some of these processes appearing to interact in a conflicting manner. This makes the search for novel therapeutic approaches difficult. New findings from the research group led by Kiemer are helping to shed light on the complexity of some of these processes.

It has been known for some time that, in NSCLC, the tumor cells exhibit lipid and cholesterol levels far higher than those in the cells of healthy tissue. Kiemer's team is the first to have demonstrated that the immune system macrophages that work with the tumor contain significantly less cholesterol than macrophages found in healthy tissue.

"The low amounts of cholesterol in the tumor-associated macrophages were a surprise, given the higher cholesterol levels that we find in the tumor tissue itself," explained Hoppstädter, the paper's lead author.
 She discovered that the genes that influence cholesterol metabolism in these macrophages are programmed differently. "The genes that regulate cholesterol uptake and the production of cholesterol in the cells are downregulated, while those that ensure that cholesterol is exported out of the macrophages are upregulated," she explained.

These new research findings corroborate what other studies have previously indicated, namely that cholesterol-lowering drugs appear not be an effective therapy against NSCLC.

"Although the lung tumor cells grow more slowly in the laboratory when treated with cholesterol-lowering drugs, this type of medication does not seem to have a particularly positive impact on the development of the disease in controlled clinical studies," Kiemer stated.

The latest results offer a possible explanation for these observations. The low level of cholesterol in the macrophages appears to contribute to lung tumor growth.

"Our results suggest that the tumor-supporting properties of the macrophages are connected to the presence of cholesterol. Cholesterol appears to be playing a critical role in the underlying regulation processes," Hoppstädter explained.

Macrophages are key defense cells within the innate immune system that each of us is born with. Normally these cells work to protect the body and to keep it healthy. Macrophages (whose name in Greek means “big eaters") engulf and destroy pathogens like bacteria or cancer cells. But some tumor cells succeed in making macrophages obey them. By reprogramming the macrophages, the tumor cells are able to make the macrophages work for them rather than against them.

"The macrophages essentially defect to the other side and begin supporting the growth of the tumor," Hoppstädter said. The reprogrammed macrophages support, for example, the formation of blood vessels, thus improving the supply of nutrients and blood to the tumor cells.

The work of the Saarbrücken researchers is helping to increase understanding of how this reprogramming occurs. They compared the processes in macrophages with a normal cholesterol metabolism with those in macrophages with an altered cholesterol metabolism.

"If the cholesterol levels in tumor-associated macrophages are normalized by preventing the efflux of cholesterol, these macrophages will stop those activities, such as revascularization, that were supporting tumor growth," Hoppstädter stated.

The researchers in Saarbrücken want to use these new results to prevent macrophages from being hijacked to support tumor growth. To pursue these studies, the team has developed a new test model. They first extracted healthy macrophages from “normal" blood donor samples, and from these they developed cell models in which the macrophages were altered so that they would behave like the defector macrophages in lung tumors.

"With our new cell model, we can carry out a very broad range of targeted studies into the processes involved," Hoppstädter said.

Normally this would require large quantities of lung carcinoma tissue, which being very difficult to source would have significantly slowed the pace of research. Over the long-term, researchers want to use the results from their basic research work for new therapeutic techniques. If successful, it could in future mean that tumor cells would be unable to recruit macrophages for support purposes, thus impeding further tumor growth.​