MIT scientists turn immune cells into cancer killers inside the body

MIT researchers have developed a new technique that allows them to transform immune cells into cancer fighters directly inside the body, potentially making advanced treatments for cancer and autoimmune diseases much easier to produce and administer. The method focuses on natural killer (NK) cells, a type of immune cell that can be engineered to recognize and destroy harmful cells. These include cancerous T cells and T cells that mistakenly attack healthy tissue, contributing to conditions such as lymphoma and autoimmune hepatitis. Rather than extracting immune cells from a patient and modifying them in a laboratory, the researchers use tiny particles made of fatty molecules to deliver genetic instructions directly to NK cells. These instructions, carried by messenger RNA, tell the cells to produce specialized proteins that help them identify and eliminate diseased T cells. The resulting cells, known as CAR NK cells, could eventually be used against several different diseases. By carrying out the engineering process inside the body, the new approach could eliminate much of the time, expense, and complexity involved in manufacturing personalized immune cell therapies. "The manufacturing challenges with CAR NK cells are significant. The idea here is you can deliver a nanoparticle that will modify your own NK cells with a CAR construct and teach them to attack tumor cells," says Daniel Anderson, a professor in MIT's Department of Chemical Engineering and a member of MIT's Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science. Anderson is the senior author of the research, published in Nature Biotechnology. The lead authors are MIT postdoctoral researcher Yuang Chen and graduate students Julia Monkovic and Haseeb Mughal. Robert Langer, MIT's David H. Koch Institute Professor, also contributed to the study. Why Current Cancer Immunotherapies Are So Complex Immune cell engineering has already transformed treatment options for certain cancers. During the past decade, the U.S. Food and Drug Administration has approved seven cancer therapies that use genetically modified T cells, known as chimeric antigen receptor (CAR) T cells. These treatments work by equipping T cells with specially designed receptors that recognize particular markers, or antigens, on other cells. When an engineered T cell encounters its designated target, such as a protein associated with cancer, it becomes activated and attacks the cell carrying that marker. CAR T cell therapies have been especially effective against blood cancers arising from B cells. These include certain forms of leukemia and lymphoma, as well as multiple myeloma. However, preparing these treatments involves several complicated steps. Doctors first collect blood from the patient and send it to a specialized facility. There, technicians separate the T cells, genetically modify them to produce the desired receptors, and grow enough engineered cells for treatment. The finished cells must then be transported back to the hospital and infused into the patient. Natural Killer Cells Offer a Different Way to Fight Cancer Scientists have recently been exploring whether natural killer cells could be engineered in a similar way. One important advantage is their potential to treat cancers and autoimmune conditions involving abnormal T cells. Trying to use CAR T cells against diseased T cells creates a major problem. Because both the engineered cells and their intended targets are T cells, the modified cells may recognize and destroy one another. This unintended attack can undermine the treatment. Natural killer cells avoid this complication because they are a different type of immune cell. They can be programmed to attack harmful T cells without triggering the same problem of engineered T cells killing each other. "NK cells can treat these T cell malignancies -- not only T cell cancer, but also T cell autoimmune diseases," Chen says. Producing CAR NK cells outside the body, however, still requires much of the specialized equipment, labor, and processing associated with CAR T cell manufacturing. To overcome these limitations, the MIT team investigated whether NK cells could instead be engineered "in vivo," meaning directly inside the body. "If a patient can just get an infusion of nanoparticles, it would dramatically simplify the process and reduce costs," Anderson says. Although researchers are actively developing CAR NK cell therapies for cancer and autoimmune disorders, none have received FDA approval. How mRNA Nanoparticles Reprogram Immune Cells The MIT team designed lipid nanoparticles (LNPs) capable of transporting messenger RNA into natural killer cells. The mRNA carries instructions for producing a chimeric antigen receptor that directs the modified immune cell toward a specific target. The technology can be adapted to recognize different proteins depending on the disease being treated. For example, the researchers can provide instructions for a receptor that recognizes CD19, a protein found on B cells, or CD3, a protein present on T cells, including those responsible for autoimmune attacks. To help the nanoparticles reach the correct immune cells, the scientists covered their surfaces with antibody fragments. These fragments recognize and attach to receptors on NK cells, helping deliver the genetic instructions where they are needed. Once inside an NK cell, the mRNA directs the production of the new receptor, giving the immune cell the ability to recognize and attack its intended target. The researchers then tested whether this approach could efficiently reprogram NK cells and whether the resulting cells could combat cancer and autoimmune disease in mice. Reprogrammed Immune Cells Eliminate Tumors in Mice The initial experiments produced encouraging results. After injecting the nanoparticles into mice, the researchers successfully modified approximately 80 percent of the NK cells they were targeting. They next investigated whether these engineered cells could attack tumors. In mice with an aggressive form of melanoma, three of the five animals treated with nanoparticles designed to direct NK cells against the cancer experienced complete remission. The researchers also tested the technique against T cell lymphoma using humanized mice. These animals receive transfusions of human blood cells, temporarily giving them immune systems that share certain characteristics with those of humans. In this model, the treatment produced substantial tumor destruction. After five injections of the nanoparticles, the tumors were completely eliminated. Importantly, these results were comparable to those achieved with CAR NK cells produced through the more traditional method of collecting NK cells, modifying them outside the body, and then returning them to the animals. This suggests that generating CAR NK cells directly inside the body could offer similar cancer-fighting capabilities while avoiding the complicated manufacturing process required by conventional cell therapies. A Single Injection Reverses Autoimmune Liver Damage The researchers also wanted to determine whether their technology could help treat autoimmune diseases, in which the immune system mistakenly damages healthy tissues. They focused on autoimmune hepatitis, a condition in which abnormal T cells attack hepatocytes, the main functional cells of the liver. By designing nanoparticles that instruct NK cells to recognize these harmful T cells, the scientists tested whether they could interrupt the autoimmune response. The treatment successfully eliminated the autoreactive T cells in mice with the disease. Even more encouragingly, the animals' damaged liver tissue healed after the harmful immune cells were removed. These improvements occurred after just one nanoparticle injection, demonstrating the potential of the approach beyond cancer treatment. "This study is an excellent example of the power of nano delivery systems and their ability to potentially treat cancer and other diseases," Langer says. A New Direction for Cancer and Autoimmune Treatments The researchers believe that reprogramming natural killer cells inside the body could eventually provide new treatment options for a much wider range of conditions. Among the diseases they hope to target are multiple sclerosis and rheumatoid arthritis, both of which can involve harmful immune responses driven by dysfunctional T cells. Although the findings are promising, the experiments were conducted in mice, and further research will be necessary to determine whether the technique is safe and effective in humans. If successful, the technology could make engineered immune cell treatments considerably more accessible by replacing a lengthy laboratory manufacturing process with the direct delivery of genetic instructions through nanoparticles. The research received funding from Sanofi, the Marble Center for Cancer Nanomedicine, and a Koch Institute Support (core) Grant from the National Cancer Institute.