The new approach uses natural cancer-targeting immune cells, known as natural killer cells, that have been modified to selectively target lymphoma. As described in their study, published in the journal Angewandte Chemie, the modified natural killer cells brought about a dramatic reduction of lymphoma in a mouse.

“We found a way to achieve selectivity in targeting lymphoma cells, which is an important departure from existing therapies,” says co-senior author Peng Wu, PhD, an associate professor in the Department of Molecular Medicine at Scripps Research.

Wu and his lab collaborated in the study with the lab of co-senior author James Paulson, PhD, the Cecil H. and Ida Green Professor and Chair of the Department of Molecular Medicine at Scripps Research.

More than 20,000 people in the United States die of lymphomas annually, while approximately 85,000 people are newly diagnosed. Most lymphomas arise from B cells, an important type of lymphocyte whose primary function is to make antibodies.

Some existing lymphoma treatments, including B-cell-killing antibodies and so-called CAR-T cell therapies, work by targeting B cells indiscriminately, largely wiping them out. However, this strategy brings many adverse side effects, including months of immunosuppression due to low antibody levels.

Wu, Paulson and their teams have developed a more specific approach using natural killer cells, which are immune cells that normally patrol the bloodstream and tissues, seeking and destroying virus-infected or cancerous cells. These immune-system warriors, also known as NK cells, are able to recognize certain tell-tale surface molecules that signify serious damage or malignancy within a cell; they can then kill that target cell through a variety of means, including by secreting proteins that punch holes in the cell’s outer membrane.

Creating a super-powered NK cell

In the early 1990s, Canadian researchers developed a special type of NK cell, NK-92, from a patient with a rare NK-cell cancer. NK-92 cells are relatively easy to grow and multiply in the lab, compared with normal NK cells found in human blood.

The Canadian researchers and others have since shown that NK-92 cells are good at killing different kinds of cancerous cells, and can bring about dramatic results in some patients, with minimal side effects. NK-92MI cells, an easier-to-multiply version of NK-92 cells, are now being widely investigated for use against various cancers.

On their own, NK-92MI cells may not be ideal cancer-fighters, especially not for advanced malignancies, in part because they are dispersed throughout the body when infused into the bloodstream. In the new study, however, Wu and his team used chemistry techniques to modify NK-92MI cells to concentrate their cancer-fighting power against lymphoma.

Steering powerful cells where they’re needed most

In an initial set of experiments, the Scripps Research scientists re-engineered NK-92MI cells to include a surface molecule that binds to a B-cell surface receptor called CD22, which is normally abundant on B-cell-derived lymphoma cells. Thus, in principle, the NK-92MI cells would selectively recognize cancerous B cells.

In cell-culture tests, the modification brought a big improvement in the NK cells’ ability to kill lymphoma cells, and these killer cells did not harm healthy cells. In a mouse model of lymphoma, however, the strategy didn’t work so well, apparently because the NK cells still did not go where they were needed.

“We found that after being injected, these NK cells tend to be found in the lungs and throughout the bloodstream — whereas in this mouse model and in human lymphoma patients, the lymphoma cells are mostly in the bone marrow,” Wu says.

The team then added to their NK cells a new molecule called Sialyl-Lewis X, which made the cells gather in bone marrow amid the lymphoma cells. This led to a dramatic delay in the development of lymphoma in the mice. With this promising result, Wu and his lab now are continuing to develop this and related strategies for clinical use.

Wu and Paulson suspect that in general, adding homing molecules such as Sialyl-Lewis X to cell-based anticancer treatments enhances the cancer-killing power at the site of the cancer, and may be a key to these treatments’ future success — particularly against solid tumors and other highly localized cancers.

Wu notes, too, that Sialyl-Lewis X, which made the NK-92MI cells gather in bone marrow, as well as the CD22-binding molecule that directed the cells to malignant B cells, are both sugar-like “glycan” molecules. Although such molecules are found on virtually all cells, and often have essential biological functions as well as crucial roles in disease, they are difficult to study and thus have been relatively neglected.

“People are only starting to appreciate the importance of glycans,” says Senlian Hong, PhD, the first author of the study and a postdoctoral research associate in the Wu lab at Scripps Research.

Funding was provided by the National Institutes of Health (R01AI143884, R01GM113046, P41GM103390, P01GM107012, R01GM130915, R01AI050143, P01HL107151, U19AI136443) and the Danish National Research Foundation (DNRF107).

In a new study, Scripps Research scientists have devised a way to deactivate these designer drugs after they’ve been administered — offering a potential path for treating addiction and overdose.

The research appears today in the American Chemical Society’s open access journal JACS Au, with findings from the laboratory of Kim Janda, PhD, the Ely R. Callaway, Jr. professor of chemistry at Scripps Research. Janda and his team developed a vaccine that was able to broadly counter the effects of synthetic cannabinoids in rodents, sequestering the drug molecules before they could interact with the central nervous system. Importantly, the approach worked in models that simulated smoking and vaping, which is how the drugs are most commonly used in real life.

“Synthetic cannabinoids are much more powerful and toxic than users often realize, and their rising prevalence has led to serious health issues among young people and adults,” Janda says. “We found a way to negate the dangerous effects of these drugs, even when they’re consumed in impure forms, as is often the case. Our hope is that this may one day help treat cannabinoid use disorders or accelerate recovery for people who overdosed.”

Not to be confused with marijuana

Synthetic cannabinoids act on the same brain cell receptors as THC, the mind-altering ingredient in marijuana. However, they’re human-made in a laboratory, with chemical structures that don’t look anything like THC. Moreover, their actual effects can be unpredictable and, in some cases, fatal, Janda says.

The synthetic drugs are often sprayed on dried plant materials so they can be smoked, or sold as vaping liquids to be inhaled using e-cigarettes. Manufacturers tend to sell the products in colorful foil packages and plastic bottles under a wide variety of brand names, including Spice, K2, Joker, Black Mamba and hundreds of others.

Synthetic cannabinoids are also sometimes mixed with other dangerous drugs such as fentanyl, which can make them more deadly. Overdoses are on the upswing, as evidenced by calls to poison control centers.

“The drugs often called synthetic marijuana are, in reality, very different from marijuana,” the American Association of Poison Control Centers says. “They contain powerful chemicals and can cause severe, life-threatening health effects: severe agitation and anxiety, nausea, vomiting, seizures and hallucinations. The drugs are made specifically to be abused. Like many other illegal drugs, synthetic marijuana is not tested for safety, and users don’t know exactly what chemicals they are putting into their bodies.”

Expanding on a proven method

For the study, Janda says first author Mingliang Lin, a graduate student, wanted to explore whether a vaccine could work against synthetic cannabinoids, just as they have shown to do against some other drugs of abuse. Janda already has developed vaccine-based approaches to combat heroin, fentanyl and cocaine.

As an addiction treatment, Janda believes vaccines provide benefits over other therapeutics, as they don’t require taking a daily pill and can reduce the risk of an overdose if the user relapses.

The newest vaccine differs from Janda’s previous work in that it’s composed of multiple drug-like antigens that stimulate “broadly neutralizing” antibodies within the body, which disable many types of cannabinoids. This is key, as synthetic cannabinoids encompass a wide range of human-made chemicals.

In behavioral experiments involving mice, the team found that even when exposed to a large amount of the drug, the vaccine offered broad protection against the psychoactive effects. The team also developed a version of the vaccine that could be inhaled, which could offer greater convenience.

“This work provides a solid foundation for future therapeutic development against synthetic cannabinoid abuse,” Janda says. “The ultimate goal is to provide prolonged protection for those who may be struggling with substance abuse.”

The study, “Broadly Neutralizing Synthetic Cannabinoid Vaccines,” is authored by Mingliang Lin, Jinny Claire Lee, Steven Blake, Beverly Ellis, Lisa Eubanks and Kim Janda.

The project was supported by the Skaggs Institute for Chemical Biology at Scripps Research.

Countries with higher proportions of Internet users tend to have more people who are willing to emigrate. At the individual level, the association between Internet use and intention to migrate is stronger among women and those with less education. The same result was found for economic migrants compared to political migrants, according to the team of international researchers from McGill University, University of Oxford, University of Calabria, and Bocconi University.

“The digital revolution brought about by the advent of the Internet has transformed our societies, economies, and way of life. Migration is no exception in this revolution,” says co-author Luca Maria Pesando, an Assistant Professor in the Department of Sociology and Centre on Population Dynamics at McGill University.

In the study, published in Population and Development Review, the researchers tracked Internet use and migration pathways with data from the World Bank, the International Telecommunication Union, the Global Peace Index, the Arab Barometer, and the Gallup World Poll, an international survey of citizens across 160 countries.

Their findings underscore the importance of the Internet as an informational channel for migrants who leave their country in search of better opportunities. Unlike political migrants, who might be pushed, for example, by the sudden explosion of a civil conflict, economic migrants’ decisions are more likely to benefit from access to information provided by the Internet, and more likely to be shaped by aspirations of brighter futures in their destination countries.

“The Internet not only gives us access to more information; it allows us to easily compare ourselves to others living in other — often wealthier — countries through social media,” says Pesando.

Case study of Italy

Looking at migration data in Italy — a country that has witnessed sizeable increases in migrant inflows over the past two decades — the researchers found a strong correlation between Internet use in migrants’ countries of origin, and the presence of people from that country in the Italian population register in the following year. Tracking migrants including asylum seekers and refugees passing through the Sant’Anna immigration Centre in Calabria, the researchers also found a link between migrants’ digital skills and knowledge of the Internet and voluntary departure from the Centre in search of better economic opportunities.

“Our findings contribute to the growing research on digital demography, where Internet-generated data or digital breadcrumbs are used to study migration and other demographic phenomena,” says Pesando. “Our work suggests that the Internet acts not just as an instrument to observe migration behaviors, but indeed actively supports the migration process.”

As next steps, the research team, which includes Francesco Billari of Bocconi University and Ridhi Kashyap and Valentina Rotondi of University of Oxford, will explore how digital technology and connectivity affect social development outcomes, ranging from women’s empowerment to reproductive health and children’s wellbeing across generations.

Story Source:

Materials provided by McGill University. Note: Content may be edited for style and length.