Blocking Cancer Cells’ Use of Sugar to Boost Immune Cells

Cancer cells and immune cells share something in common: They both love sugarSugar is an important nutrient. All cells use sugar as a vital source of energy and building blocks. For immune cells, gobbling up sugar is a good thing, since it means getting enough nutrients to grow and divide for stronger immune responses. But cancer cells use sugar for more nefarious ends. So, what happens when tumor cells and immune cells battle for access to the same supply of sugar? That’s the central question that Memorial Sloan Kettering (MSK) researchers Taha Merghoub,Jedd Wolchok, and Roberta Zappasodi explore in a new study published in the journal Nature.

Using mouse models and data from human patients, the researchers found a direct relationship between the amount of sugarspecifically glucose — that a tumor consumes and the effectiveness of immunotherapy: The more sugar the tumor consumed, the less effective the immunotherapy. The findings suggest that blocking cancer cells’ use of sugar could tip the scales in favor of immune cells, especially when they are activated by immunotherapy drugs.

If we reduce a tumor’s use of glucose, then we free up more of it for immune cells to use, which benefits the immune response,” says Dr. Merghoub, who co-led the research effort.

What we think we’ve identified is a new means to improve checkpoint blockade immunotherapy,” adds Dr. Wolchok. Immune checkpoint inhibitors release the brakes on immune cells and can provide lasting benefits for people with cancer, but they do not work for everyone. The new research may provide a way to boost their effectiveness.

Dr. Wolchok, Chief of the Immuno-Oncology Service in the Human Oncology and Pathogenesis Program at MSK, also directs the Parker Institute for Cancer Immunotherapy at MSK and co-directs the Ludwig Center for Cancer Immunotherapy at MSK.

Source: https://www.mskcc.org/

Smart Nanoparticles To Target Lung Cancer

A new and promising approach for treatment of lung cancer has been developed by researchers at Lund University (Sweden). The treatment combines a novel surgical approach with smart nanoparticles to specifically target lung tumorsLung tumors are often difficult to remove using current surgical techniques due to their location in the lung or the fact that there are multiple tumors which are too small to observe. Tumors also develop natural barriers to prevent drugs and immune cells from reaching the tumor cells.

Illustration of the pH-responsive mesoporous silica nanoparticles designed to specifically target lung cancer

Therefore, patients often receive high doses of chemotherapeutics which are circulated through the entire body and lead to major side effects in other organs. While a number of new experimental therapies have been developed for lung cancer and have shown promise in the lab, a major remaining challenge has been how to deliver the right drug specifically to these difficult to reach tumors”, explains Darcy Wagner, Associate Professor and Head of the research group.

In order to overcome this challenge, the researchers behind the new study: Deniz Bölükbas and Darcy Wagner, researchers of the Lung Bioengineering and regeneration group, and colleagues developed a novel surgical technique which introduces the nanoparticles only into the blood vessels of the lung. The blood vessels around and in tumors are different than those in normal organs. The researchers used this difference to their benefit to direct nanoparticles to the interior of large and dense solid lung tumorsBölükbas and colleagues also used animal models which have a full immune system and closely resemble the types of lung tumors that patients have.

Using this technique, which we call ‘organ restricted vascular delivery’ (ORVD), we were able to see lung cancer cells with the delivered nanoparticles inside of them – something which has not been achieved previously in these types of lung cancer animal models, which closely resemble the clinical scenario”, explains Deniz Bölükbas, post-doctoral fellow and leading author of the article.

The new study has been published in the July issue of Advanced Therapeutics.
Source: https://www.lunduniversity.lu.se/

How To Turn Tumors Into Cancer Vaccine Factories

Researchers at Mount Sinai have developed last year a novel approach to cancer immunotherapy, injecting immune stimulants directly into a tumor to teach the immune system to destroy it and other tumor cells throughout the body.
The “in situ vaccination” worked so well in patients with advanced-stage lymphoma that it is also undergoing trials in breast and head and neck cancer patients, according to a study published in Nature Medicine in April.
The treatment consists of administering a series of immune stimulants directly into one tumor site. The first stimulant recruits important immune cells called dendritic cells that act like generals of the immune army. The second stimulant activates the dendritic cells, which then instruct T cells, the immune system’s soldiers, to kill cancer cells and spare non-cancer cells. This immune army learns to recognize features of the tumor cells so it can seek them out and destroy them throughout the body, essentially turning the tumor into a cancer vaccine factory.

The in situ vaccine approach has broad implications for multiple types of cancer,” said lead author Joshua Brody, MD, Director of the Lymphoma Immunotherapy Program at The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai. “This method could also increase the success of other immunotherapies such as checkpoint blockade.”

After testing the lymphoma vaccine in the lab, it was tested in 11 patients in a clinical trial. Some patients had full remission from months to years. In lab tests in mice, the vaccine drastically increased the success of checkpoint blockade immunotherapy, the type of immunotherapy responsible for the complete remission of former President Jimmy Carter’s cancer and the focus of the 2018 Nobel Prize in Medicine.

Source: https://www.mountsinai.org/

How To Starve Cancer Tumors and Beef Up The Immune Cells

Tumors are hogs, gobbling nutrients to fuel their runaway growth, and for decades researchers have tried to develop drugs that cut off their food supply. A study out today shows that an updated version of a failed cancer drug can not only prevent tumor cells from using an essential nutrient, but also spur immune cells to attack the growths.

T lymphocyte cells attacking a cancer cell, computer illustration. T lymphocytes are a type of white blood cell that recognise a specific site (antigen) on the surface of cancer cells or pathogens and bind to it. Some T lymphocytes then signal for other immune system cells to eliminate the cell. The genetic changes that cause a cell to become cancerous lead to the presentation of tumour antigens on the cell’s surface.

It’s a pretty striking paper,” says cancer biologist Ralph DeBerardinis of the University of Texas Southwestern Medical Center in Dallas, who wasn’t connected to the study. “With a single drug, you can in effect starve the tumor and beef up the immune cells.”

Cancer cells eat to obtain molecules vital for survival and replication, but their gluttony also turns their surroundings into an acidic, oxygen-deprived moat that stymies immune cells trying to eliminate them. One of the nutrients many tumors need in abundance is the amino acid glutamine, which provides the building blocks for fabricating molecules such as DNA, proteins, and lipids. “Glutamine is incredibly important for cellular metabolism,” says immunologist Jonathan Powell of the Johns Hopkins School of Medicine in Baltimore, Maryland.

Starting in the 1950s, researchers tried to turn tumors’ glutamine dependence against them, developing drugs to block its metabolism. A bacteria-derived compound called DON, for instance, kills tumors by inhibiting several enzymes that allow cancer cells to use glutamine. In clinical trials, however, the drug provoked severe nausea and vomiting, and it was never approved.

Now, Powell and colleagues have crafted a new version of DON that may be easier to stomach. It carries two chemical groups that keep it inert until it reaches the tumor’s neighborhood. There, enzymes that normally loiter around tumors remove these molecular handcuffs, unleashing the drug on the cancerous cells. With this approach, “the vast majority of the active drug is where we want,” Powell says.

To test their new compound, he and colleagues injected four types of cancer cells into mice, inducing tumors. They then dosed some of the animals with their next-generation DON. The drug worked against all four kinds of tumors, the scientists report today in Science. In untreated mice, for example, colon cancer tumors had grown more than five times larger after about 3 weeks. But in rodents that received DON, the tumors shrank and almost disappeared. The researchers found that the drug wasn’t just throttling glutamine metabolism. It was also disrupting other aspects of the cellsbiochemistry, such as their ability to use the sugar glucose.

Source: https://www.sciencemag.org/

Nanoparticle Targets Tumor-infiltrating Immune Cells, Flips Switch Telling Them To Fight

Immunotherapy’s promise in the fight against cancer drew international attention after two scientists won a Nobel Prize this year for unleashing the ability of the immune system to eliminate tumor cells.

But their approach, which keeps cancer cells from shutting off the immune system’s powerful T-cells before they can fight tumors, is just one way to use the body’s natural defenses against deadly disease. A team of Vanderbilt University bioengineers today announced a major breakthrough in another: penetrating tumor-infiltrating immune cells and flipping on a switch that tells them to start fighting. The team designed a nanoscale particle to do that and found early success using it on human melanoma tissue.

Tumors are pretty conniving and have evolved many ways to evade detection from our immune system,” said John T. Wilson, assistant professor of chemical and biomolecular engineering and biomedical engineering. “Our goal is to rearm the immune system with the tools it needs to destroy cancer cells. “Checkpoint blockade has been a major breakthrough, but despite the huge impact it continues to have, we also know that there are a lot of patients who don’t respond to these therapies. We’ve developed a nanoparticle to find tumors and deliver a specific type of molecule that’s produced naturally by our bodies to fight off cancer.

That molecule is called cGAMP, and it’s the primary way to switch on what’s known as the stimulator of interferon genes (STING) pathway: a natural mechanism the body uses to mount an immune response that can fight viruses or bacteria or clear out malignant cells. Wilson said his team’s nanoparticle delivers cGAMP in a way that jump-starts the immune response inside the tumor, resulting in the generation of T-cells that can destroy the tumor from the inside and also improve responses to checkpoint blockade.

While the Vanderbilt team’s research focused on melanoma, their work also indicates that this could impact treatment of many cancers, Wilson said, including breast, kidney, head and neck, neuroblastoma, colorectal and lung cancer.

The findings are reported in the journal Nature Nanotechnology.

Source: https://news.vanderbilt.edu/