Modified T cells fight cancer

When a person is suffering from cancer, conventional treatments like radio- and chemotherapy or surgical interventions are often not sufficient as cures or a means of improving the prognosis. However, in recent years researchers have been placing high hopes on a new form of treatment to fight cancer: immunotherapy. This approach is revolutionary because it does not attack tumors directly but supports the patient’s own defenses in fighting the disease. Researchers led by principal investigator Thomas Blankenstein at the MDC and the Charité – Universitätsmedizin, Campus Berlin-Buch, now have succeeded in modifying cells of our immune system, enabling them to specifically track down and destroy cancer cells. They have recently published their findings in Nature Biotechnology online. Now first clinical studies are planned.

One of the main weapons of our immune system is T cells. Their surfaces possess receptors, a kind of antenna with which they can recognize foreign structures – antigens – on pathogens. The receptors enable the T cells to destroy the invaders in our bodies. At the same time, T cells are able to distinguish between the body’s own cells, recognized as “self”, and foreign cells, or “non-self”. This is important because the body’s own tissues are not supposed to be attacked. However, in the fight against cancer, this is exactly where the problem lies: T cells identify tumor cells as “self” and the immune system tolerates them.

Diese Maus produziert T-Zellen mit menschlichen Rezeptoren, die das MAGE-A1-Antigen erkennen. Foto: SFB-TR 36

“The question now is how we can circumvent this tolerance problem,“ says Thomas Blankenstein, describing the goal of T cell therapy. Thomas is principal investigator at the MDC and the Charité and led the study in Nature Biotechnology. Working with Matthias Obenaus, Matthias Leisegang, Catarina Leitão, Xiaojing Chen, Ioannis Gavvovidis (all of the MDC), Pierre van der Bruggen (Bruxelles), Wolfgang Uckert (Humboldt-Universität zu Berlin und MDC) und Dolores Schendel (Medigene AG, Planegg/Martinsried), he has now found a solution. The team created transgenic mice that produce human T cell receptors that are effectively directed against specific tumor cells.

To accomplish this, the researchers took advantage of a process called T cell maturation that takes place in the thymus. In fact, our bodies do produce T cells with receptors directed against “self” structures, found on the cells of our body or tumor cells. Normally these are, however, sorted out, permitting only those T cells that are directed against foreign structures to leave the thymus.

The trick that Thomas and his colleagues used was to produce human T cell receptors that are directed against “self”-structures in mice. Since these human antigens are foreign to mice, the T cell receptors that are produced in response to them are not sorted out during the maturation process in the mouse. To produce these human T cell receptors, the researchers had to introduce the corresponding genes into the mouse. “This was the real challenge because we had to transfer millions of genetic letters,” Thomas says. The sequences of the genes had to be inserted into mouse embryonic stem cells in order to breed transgenic mice capable of producing human receptors.

The project, which required more than ten years of painstaking work, eventually led to success, producing transgenic mice bearing T cells with human receptors. The researchers then were able to isolate specific human T cell receptors that recognized a target antigen called MAGE-A1. This is a “self”-structure that is expressed in adults only on the surfaces of tumor cells in a number of cancers such as multiple myeloma, a malignant disease of the bone marrow, but not on healthy, vital cells. “We therefore have good reason to assume that a therapy directed against MAGE-A1 will have no or few side-effects,” Thomas says. Next, using biotechnological methods, the researchers transferred the mouse-derived human T cell receptors that target MAGE-A, into human T cells that had been extracted from human blood and raised in Petri dishes.

Finally, the researchers used a comparison to prove the efficacy of the modified T cells. The blood of some people naturally contains T cells with receptors that recognize MAGE-A1 – which apparently escape from the thymus before being sorted out. The researchers applied these natural T cells to attack tumors in a mouse model. The result was sobering: the natural T cells had only minimal effects on the tumor. This was in total contrast to the T cells that had been modified in mice to target MAGE-A1, which could cause the regression of a large tumor in mice. “These are good indicators that T cells with the receptors produced in mice might also be very effective in humans,” Thomas says.

With Antonio Pezzutto from the Charité, Thomas and his colleagues are now planning an initial clinical trial. The T cells with receptors modified to target MAGE-A1 will be reinfused into patients with multiple myeloma as a test of their safety and efficacy. Currently the researchers are awaiting approval for human trials using the procedure. Once it has been attained, the project will represent the first T cell receptor gene therapy in Germany and a potentially a huge step toward an effective immunotherapy against specific types of cancer.

- Elke Binder

Highlight Reference:

Obenaus, M., Leitão, C., Leisegang, M., Chen, X., Gavvovidis, I., van der Bruggen, P., Uckert, W., Schendel D. J., & Blankenstein, T. Identification of human T-cell receptors with optimal affinity to cancer antigens using antigen-negative humanized mice. Nature Biotechnology 33, 402–407 (2015) http://doi:10.1038/nbt.3147

Featured Image: This transgenic mouse produces T-cells with human receptors that recognize the MAGE-A1 antigen. Photo: SFB-TR 36