Targeted LNP-delivered, in vivo induced CAR-T-cell: A first-in-man proof-of-cuncept to increase patient access to cellular immunotherapies in Sweden and beyond
Delivering effective immunotherapy in a smarter way
CAR-T cell therapies, in which the body’s own immune cells are genetically modified to attack cancer cells, can save lives. However, the treatment requires high-tech laboratories and is very expensive. Researchers will now develop a simpler method – similar to the one used in mRNA vaccinations – to create CAR-T cells inside the body.
CAR-T cell therapy has revolutionised the treatment of B-cell lymphoma and B-cell leukaemia, cancers of the lymphatic system. If the standard treatment did not work, the prognosis for patients used to be very poor. Thanks to CAR-T cell therapy, survival rates after one year have increased up to 80%, but treatment is extremely resource-intensive.
“This means that not everyone who needs the treatment can get it. It is associated with significant costs and logistical problems,” says Samir El Andaloussi, professor at Karolinska Institutet.
Along with a number of other researchers, he will now receive funding from the Sjöberg Foundation for a flagship project that aims to simplify treatment. Currently, when doctors perform CAR-T cell therapy, they remove special immune cells, T cells, from patients and these are sent to a laboratory in another part of the world.
“We put the cells on a plane, perhaps to the US, where the cells are genetically modified before being sent back to us,” says Stephan Mielke, professor at Karolinska Institutet and head of department at Karolinska University Hospital, who is leading the clinical part of the project.
The T cells are modified, giving them a surface protein that allows them to bind to cancer cells. When physicians inject these genetically modified T cells into a patient’s bloodstream, they attack the cancer cells and kill them. The treatment is incredibly effective, but the procedure is complicated, costly and slow.
“For patients, treatment is a matter of life and death. It is black or white. But when we get the cells back after four to six weeks, this wait has been too long for some patients,” says Mielke.
To make the process simpler, cheaper and faster, the researchers will now develop a method similar to that used in the delivery of mRNA vaccines for COVID-19. They will fill tiny fat particles, lipid nanoparticles, with an mRNA that contains the code for the protein that allows T cells to destroy cancer cells. They will put an antibody on the surface of the fat particles, which makes them stick to T cells when injected into the bloodstream. The T cells will then take up the particles and, when the mRNA molecules are inside the T-cells, they start producing the protein that makes them attack the cancer cells.
“Our biggest challenge is developing good lipid nanoparticles. When they are injected into the bloodstream, they often end up in the liver and other organs. We need to optimise them so that more end up in tissues where T cells are present, such as the spleen and bone marrow,” says El Andaloussi.
The researchers will investigate how well the T cells take up the lipid nanoparticles in animal models and in three-dimensional cell models of human tonsils and spleen, called organoids.
Once the fat particles are good enough and have been proven safe to use in animal experiments, the team will start clinical trials in humans. The researchers believe that many patients will benefit from the treatment if it works. B cells can cause not only cancer, but also autoimmune diseases. For example, in one study, researchers have seen evidence that a traditional CAR-T cell therapy may work as a treatment for systemic lupus erythematosus.
Depending on how researchers design the antibody on the lipid nanoparticle’s surface and the mRNA within the particle, the treatment can target various cancers and other diseases.
“We are working on what is a completely new technology, which can be used for diseases where some type of genetic modification is necessary,” says Mielke.
The research team:
Samir El Andaloussi, professor, Karolinska Institutet, preclinical project leader
Stephan Mielke, professor and senior consultant, Karolinska Institutet and Karolinska University Hospital, clinical project leader
Gunilla Enblad, professor and senior consultant, Uppsala University and Uppsala University Hospital
Marcus Buggert, docent, Karolinska Institutet
Fredrik Höök, professor, Chalmers University of Technology