Translational Archives - V Foundation

Britta Will, PhD

Acute myeloid leukemia (AML) is a deadly blood cancer that starts in the bone marrow, where our blood cells are made. This cancer is especially dangerous for people over 65 – more than 9 out of 10 patients die from it. The treatments we have now work for a while, but then they stop working. This happens because some cancer cells are tough and can survive the treatment, causing the cancer to come back. Scientists have discovered something important about how these cancer cells survive. They found that the way cancer cells use iron helps them fight off treatment. Iron is a mineral our bodies need, but cancer cells change how they handle iron to stay alive when doctors try to kill them. We believe that iron helps cancer cells resist drugs that are supposed to make them grow into normal, healthy blood cells. We made an exciting discovery: when they used drugs that grab onto iron, the cancer cells became much easier to kill with regular treatments. This seems to work on many different types of this blood cancer, even the hardest ones to treat. We plan to test this new approach by mixing iron-grabbing drugs with current treatments. We will use real cancer cells from patients to see if this combination works better. We want to find out if it can really get rid of the cancer stem cells (the “parent” cells that keep making more cancer). If this research works, doctors could have a new way to treat older patients with this blood cancer. Many older patients can’t get bone marrow transplants because they’re too risky. By targeting how cancer cells use iron, doctors might be able to beat treatment resistance and help patients live longer without using harsh chemotherapy drugs.

Chonghui Cheng, MD, PhD

Cancer vaccines are a promising new treatment that help the immune system find and destroy cancer cells. These vaccine work by teaching the body to recognize special signals, called neoantigens, that appear only on cancer cells. Most cancer vaccines today use neoantigens caused by changes in DNA. But because these changes are different for each person, it is hard to make a vaccine that works for everyone. Our research aims to develop a more widely useful cancer vaccine for triple-negative breast cancer (TNBC), a fast-growing and hard-to-treat cancer. We are studying a new type of neoantigens, that comes from a mistake in how cells process RNA. Normally, cells remove parts of RNA called introns before making proteins. But in some cancer cells, this process fails when a protein called hnRNPM is missing. As a result, the introns stay in, leading to unusual protein pieces that the immune system can recognize and attack. Our team includes experts in RNA, data science, and vaccine development. We are working together to find common neoantigens in TNBC that come from faulty introns and to make a strong mRNA cancer vaccine. We will look for the most common neoantigens made this way in TNBC and build better tools to find neoantigens that current methods miss. We will create mRNA vaccines that teach the immune system to attack these cancer signals. If this works, the vaccine could help treat TNBC and possibly other cancers that make the same neoantigens.

Djordje Atanackovic, MD

T cell acute lymphoblastic leukemia (T-ALL) is a serious cancer that affects part of the immune system called T cells. It’s especially hard to treat in adults, and current treatments often don’t work well. A special treatment called CAR T cell therapy—where doctors change a patient’s own immune cells to fight cancer—has worked well for some other types of cancer. But using it for T-ALL has been very difficult. One problem is that the CAR T cells can accidentally attack healthy T cells, and sometimes even attack each other.We recently identified a new target called CD229, a marker found on both cancerous and some healthy T cells. We made CAR T cells that attack cells with CD229. The exciting part is that these new CAR T cells can still kill cancer cells but don’t harm as many healthy T cells. This is because healthy T cells lower the amount of CD229 when they are activated, so they are not attacked.We improved our CAR T cells even more by making them less “sticky,” so they are more careful about which cells they attack. Tests in the lab and in animals showed that these new CAR T cells still fight cancer well and are safer. Now, our team is testing this treatment on real samples from many T-ALL patients. If it works, we will start a small clinical trial. This new treatment could be a big step forward, giving hope to people with T cell cancers by offering a better and safer option.

Jessica Thaxton, PhD, MsCR

T cells are part of the body’s immune system. T cells ward off disease but are also capable of fighting cancers. In fact, immune therapies in cancers have produced major gains in allowing patients with cancer to survive long-term. T cells can invade cancers, but cancers create a hostile environment that limits T cell killing capacity. This makes immune therapies function poorly. We have discovered a pathway in T cells that is engaged by the hostile environment of tumors that induces T cell distress and death. We have found a group of drugs that inhibit this pathway. These drugs also protect T cells from sensing the stressful environment of cancer. This group of drugs allows T cells to live longer and fight harder to eliminate cancer. We have found that these drugs improve the long-term outcomes of immune therapies and hold potential to increase the number of patients cured of cancer when treated with immune therapy. This project plans to study this stress pathway in T cells in samples from patients with cancer and to test these drugs in several models so that they can be used in the clinic to fight cancer in patients.

Andrew Brenner, MD PhD

Some cancers can spread to the fluid that surrounds the brain and spine. This is called leptomeningeal metastases, or LM. It is a serious and often deadly problem. Today, there are very few treatments that work well for this condition.Our team is studying a new treatment called Rhenium Obisbemeda (186RNL). This treatment sends tiny amounts of radiation straight into the spinal fluid, where it can kill cancer cells. Unlike standard radiation, which can hurt healthy parts of the brain, this method targets cancer cells more carefully and reduces damage to normal tissue.In our research, we are collecting samples from patients to see how their cancer and immune cells respond to this treatment over time. We are also using lab models to test whether this radiation works better when combined with other treatments—like drugs that help the body’s immune system fight cancer or block cancer cells from fixing themselves.Our goal is to find safer and more effective ways to treat LM and possibly other hard-to-treat cancers. This research could lead to better options for people with advanced cancer, giving them more time and better quality of life.

William Freed-Pastor, MD, PhD

Pancreatic cancer is a terrible disease, and we urgently need better treatments. The immune system can search the entire body to find and destroy cancer cells, just like it protects us from viruses or bacteria. The immune system does this by recognizing small “flags” on the surface of cancer cells. Unfortunately, cancer cells can often “hide” from the immune system so they don’t get destroyed. We urgently need to find new ways to use the immune system to fight pancreatic cancer to develop better treatments for patients. We’ve been using something called “organoids” to study pancreatic cancer. These are tiny, 3D versions of tumors grown in a dish from a patient’s own cancer cells. Using these organoids, we’ve been able to identify the “flags” on the surface of pancreatic cancer cells that the immune system might be able to recognize. We’ve also created a special system to help us figure out which of these “flags” are the best ones for the immune system to fight and ultimately destroy the tumor. Our plan is to use what we’ve learned to carefully test many new targets on the surface of pancreatic cancers to see if the immune system can recognize them. This will help us develop improved therapies for pancreatic cancer patients.

Andrea Kasinski, PhD

We are developing a new cancer treatment that could change how we fight the disease. Our drug, FM-FolamiR-34a, is designed to treat triple-negative breast cancer (TNBC). TNBC is one of the most aggressive and hardest-to-treat types of cancer. Many cancer treatments attack a single target, but our drug works differently. It stops multiple targets at once, like a combination of drugs in a single treatment. It does this by replacing a natural tumor-fighting molecule that is missing in many TNBC cases.Earlier attempts to use this type of treatment failed because the drug broke down too quickly and did not reach tumors well. We have solved this problem by making the drug more stable and attaching it to a targeting molecule that guides it directly to cancer cells.In lab studies, this approach shrank tumors and, in some cases, made them disappear completely. To prepare for human trials, we will improve the drug, compare it to existing treatments, and complete important safety tests.This research could lead to a powerful new way to treat cancer, offering hope to patients who currently have few options. Our goal is to turn cutting-edge science into real treatments that save lives.

Jacalyn Rosenblatt, MD

Multiple myeloma is a type of cancer that affects plasma cells. This disease can lead to infections, kidney problems, and bone pain or fractures. There have been great improvements in the treatment of multiple myeloma in recent years. However, most people are still not cured by current therapy. Treatments that use the immune system have shown great promise. One important example is CAR T-cell therapy. CAR T cells are made by taking a patient’s T cells (a type of immune cell), and changing them so they can recognize and kill cancer cells. These cells are then given back into the patient by an intravenous infusion. CART cell therapy has resulted in dramatic improvements in outcomes for patients with multiple myeloma. Our group has studied a new combination approach to improve upon responses to CART cell therapy. We have developed a personalized cancer vaccines using a patient’s own cancer cells. To make the vaccine, a patients plasma cells are collected from the bone marrow and are combined with immune cells called dendritic cells, which help activate the immune system. In a national study, this vaccine was shown to be safe, could be made at centers across the country, and was shown to stimulate immune responses. In this new study will test the vaccine in combination with CAR T-cell therapy. This DC/MM fusion vaccine has the potential to stimulate a broad immune response, preventing the development of resistance and can expand the CART cells to enhance their durability and effect.

Tannishtha Reya, PhD

Acute Myelogenous Leukemia (AML) is a fast-growing cancer of the blood and is the most common type in adults. Unfortunately, current treatments often don’t work well, and many patients get sick again or die. That’s why new and better treatments are needed. In our research, we looked at a protein that is found in large amounts on the outside of leukemia cells. Our earlier studies showed that this protein is needed for the cancer to grow. Because it’s on the outside of the cell, we can try to block it using special tools called antibodies. These antibodies attach to the protein and stop it from working. Here, we propose to develop an antibody that is able to target the protein and stop the cancer cells from growing. If we are successful, we plan to test the antibody in patients who are newly diagnosed or who haven’t gotten better with current treatments. This new antibody treatment could be a powerful new way to help people with AML live longer and healthier lives.

Jennifer McQuade, MD

Immunotherapy is a type of cancer treatment that helps the body’s immune system fight cancer. It has changed how we treat many cancers. But not all patients benefit from it. So, we need new ways to make this treatment work better. One area of interest is the gut microbiome. This is the group of trillions of bacteria that live in our gut. These bacteria can affect how the immune system works and how well immunotherapy works. Our research, and that of others, has shown that people who respond to immunotherapy have different gut bacteria than those who do not. Diet plays a big role in shaping the gut microbiome, as the bacteria in our gut eat what we eat. We have shown that diet is linked to how well people respond to immunotherapy. In mice, changing the diet changed both the gut bacteria and the response to treatment. Now, we are testing if diet changes can help patients who are starting immunotherapy. We want to see if we can improve their gut bacteria and boost their immune response through their diet. If this works, it could be a simple and low-cost way to help more people benefit from immunotherapy. We also found that a plant-based, high-fiber diet lowers certain bile acids in the body; these acids may weaken the patient’s immune response. In this study, we will test if these bile acids can be used as a marker of the extent to which the diet and treatment are working.